Preparation of docetaxel long-circulating liposome and freeze-dried powder injection thereof

A long-circulating liposome and docetaxel technology, which is applied to freeze-dried powder injection and its preparation, contains insoluble anticancer drug docetaxel long-circulating liposome field, can solve the problem of hindering liposome, stable It can improve the drug loading and stability, reduce unsafe factors, and have excellent storage stability.

Active Publication Date: 2008-12-17
HAINAN SIMCERE PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although PEGylated liposomes can increase the circulation time of liposomes in the blood, due to the presence of PEG, new toxic effects have emerged, such as liposome formulations containing PEGylated phospholipids can cause Cutaneous toxicity, commonly known as "hand-foot syndrome," which causes rashes/sores on the palms and soles of the feet
Another disadvantage of PEGylated liposomes is the presence of macromolecules (polyethylene glycol) on the liposome surface, which may weaken liposome-cell interactions and prevent liposome entry into tumor tissue , thus potentially reducing the accumulation of liposomal drugs in tumor tissue
[0005] The docetaxel liposome drug content reported by people such as Maria Laura Immordino is only 0.75mg/mL, and the stability is poor, and 4 ℃ places one day and just leaks more than 50% (Maria Laura Immord

Method used

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  • Preparation of docetaxel long-circulating liposome and freeze-dried powder injection thereof
  • Preparation of docetaxel long-circulating liposome and freeze-dried powder injection thereof
  • Preparation of docetaxel long-circulating liposome and freeze-dried powder injection thereof

Examples

Experimental program
Comparison scheme
Effect test

Example Embodiment

[0053] Example 1

[0054] Preparation prescription (100mL capacity)

[0055] Docetaxel 100mg

[0056] Soybean Lecithin (SPC) 1.5g

[0057] Distearoylphosphatidylglycerol (DSPG) 150mg

[0058] Cholesterol 600mg

[0059] a-tocopherol 17mg

[0060] Sucrose about 10g

[0061] Sodium citrate about 294mg

[0062] Citric acid

[0063] Adjust the volume of water for injection to the required volume

[0064] The preparation process is as follows:

[0065] According to the formula, select soybean phospholipids, distearoylphosphatidylglycerol, cholesterol and a-tocopherol, dissolve them in chloroform solution and mix them evenly; use spray drying to remove chloroform under reduced pressure to form a lipid mixture; prepare 0.01M sodium citrate solution , Dissolve sucrose in sodium citrate solution as a hydration solution, the hydration temperature is generally between 55 ℃ ± 5 ℃, multi-compartment liposome suspension; after hydration is complete, homogenize to an average with a high-pressure ...

Example Embodiment

[0066] Example 2

[0067] Preparation prescription (100mL capacity)

[0068] Docetaxel 200mg

[0069] Egg yolk lecithin (EPC) 4g

[0070] Dimyristoylphosphatidylglycerol (DMPG) 1g

[0071] Cholesterol 1g

[0072] a-Tocopheryl succinate 90mg

[0073] Lactose about 10g

[0074] Sodium succinate about 800mg

[0075] Succinic acid

[0076] Adjust the volume of water for injection to the required volume

[0077] The preparation process is as follows:

[0078] According to the formula, select egg yolk lecithin, dimyristoylphosphatidylglycerol, cholesterol, and a-tocopheryl succinate dissolved in a chloroform-methanol (2:1) solution and mix well; remove the organic solvent under reduced pressure by evaporation under reduced pressure , To form a lipid mixture; prepare a 0.03M sodium succinate solution, dissolve lactose in the sodium succinate solution as a hydration solution, the hydration temperature is generally 65 ℃ ± 5 ℃, multicompartment liposome suspension; After hydration is comple...

Example Embodiment

[0079] Example 3

[0080] Preparation prescription (100mL capacity)

[0081] Docetaxel 400mg

[0082] Distearoylphosphatidylcholine (DSPC) 12g

[0083] Distearoylphosphatidylglycerol (DMPG) 2.4g

[0084] Cholesterol 6g

[0085] a-tocopherol 100mg

[0086] Trehalose about 20mg

[0087] Phosphate about 1.5g

[0088] Adjust the volume of water for injection to the required volume

[0089] The preparation process is as follows:

[0090] According to the formula, select distearoyl phosphatidyl choline, distearoyl phosphatidyl glycerol, cholesterol and a-tocopherol, dissolve in chloroform-methanol (2:1) and mix well; remove the solvent by spray drying to form fat Mixture of substances; prepare 0.05M phosphate buffer solution, dissolve trehalose in phosphate solution as a hydration solution, the hydration temperature is generally 45 ℃ ± 5 ℃, multilamellar liposome suspension; after complete hydration Use a high-pressure homogenizer to homogenize to an average particle size of 80±10nm, us...

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Abstract

The invention discloses a preparation technique of non-pegylation docetaxel long-circulating liposome which meets clinical and large-scale production requirements and a freeze-dried powder-injection; the liposome consists of docetaxel, neutral phospholipid, charged phospholipid, cholesterin, antioxidant, excipient, buffering agent and water for injection; the preparation technique includes the following steps: preparing multivesicular liposome, homogenizing the liposome, fixing volume, sterilizing, split charging, freeze drying, etc. The liposome increases the solubility of drugs, overcomes poor stability of docetaxel injection and toxicity caused by complex solvent and prolongs the in vivo circulating time of drugs; compared with pegylation long-circulating liposome, the toxicity is decreased and the inhibiting effect on tumor cells is strengthened.

Description

technical field [0001] The invention belongs to the field of pharmaceutical preparations, and relates to a long-circulating liposome containing an insoluble anticancer drug docetaxel, a freeze-dried powder injection and a preparation method thereof. Background technique [0002] Docetaxel is a taxane anticancer drug that is semi-synthesized from the precursor extracted from the needles of yew berry. Its anti-cancer mechanism is to stimulate the polymerization of cathelicidin, promote the assembly of microtubule dimers into microtubules, and cause cell proliferation to stop at the stage of mitotic quiescence (G2 / M). FDA approved docetaxel for the treatment of breast cancer, ovarian cancer, non-small cell lung cancer and pancreatic cancer, and has certain effects on primary and metastatic cancers such as head and neck squamous cell carcinoma and malignant melanoma. Due to its anti-cancer mechanism and exact curative effect, it has become one of the most valuable anti-cancer d...

Claims

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Application Information

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IPC IPC(8): A61K9/127A61K9/10A61K31/337A61K47/24A61P35/00
Inventor 林巧平王青松许向阳刘春晖江征殷晓进
Owner HAINAN SIMCERE PHARMA CO LTD
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