CN101015563A - Intravenous injection microemulsion preparation of teniposide - Google Patents
Intravenous injection microemulsion preparation of teniposide Download PDFInfo
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- CN101015563A CN101015563A CNA2006101676888A CN200610167688A CN101015563A CN 101015563 A CN101015563 A CN 101015563A CN A2006101676888 A CNA2006101676888 A CN A2006101676888A CN 200610167688 A CN200610167688 A CN 200610167688A CN 101015563 A CN101015563 A CN 101015563A
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- teniposide
- intravenous injection
- injection emulsion
- emulsion
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Abstract
This invention relates to a formulation and preparation method of micro emulsion of Teniposide for intravenous injection. The micro emulsion comprises active components and auxiliary materials, wherein the active components are Teniposide or mixture of Teniposide, paclitaxel, and etoposide; and auxiliary materials is composed of vegetable oil, emulsifying agent or assistant emulsifier, and organic solvent. The micro emulsion for intravenous injection is obtained by preparing active components and auxiliary materials to pre-concentration liquid and adding to 5% glucose solution for clinical use. The invention has the advatages of convenient adminstration, high bioavailability, and reduced toxic anaphylaxis.
Description
Technical field
The present invention relates to a kind of prescription and preparation of intravenous injection microemulsion preparation of teniposide.
Background technology
(teniposide is a kind of semi-synthetic derivant of podophyllotoxin VM-26) to teniposide, belongs to the antitumor drug of plant origin.It is the period specific cell toxicity medicament, suppresses the DNA topoisomerase II, causes two strands or strand to destroy making cell mitogen to be stopped at S late period or G2 early stage, thereby hinders tumour cell division, suppresses tumor growth.Teniposide is evident in efficacy, its biological activity be medicine etoposide of the same type 5-10 doubly, and clinical data shows the teniposide few side effects, toxicity is less, and liver, renal function are not had influence.Owing to have anti-tumor activity widely clinically, teniposide now is widely used in clinical treatments such as acute childhood lymphoblastic leukemia, small cell lung cancer, lymphoma and neuroblastoma, more because of its neutral lipophilic characteristic, can see through blood brain barrier, become the first-selected chemotherapeutics of clinical treatment cerebroma at present.Teniposide was used for the acute childhood lymphoblastic leukemia chemotherapy by the U.S. FDA official approval in 1992, and commodity are called VUMON .China copies at the beginning of 21 century successfully, and its commodity are called the Lay of nation.
Teniposide itself is water-soluble hardly, must be dissolved in organic solvent and use.As above-mentioned several clinical injection liquid formulations, all make solvent with organic reagents such as ethanol, separate out drug crystallization for avoiding after the dilution simultaneously, adding surfactant polyoxyethylene Oleum Ricini (CremophorEL) in the prescription is solubilizing agent.Prescription consists of: every ampere (5ml) contains teniposide 50mg, benzyl alcohol 150mg, N,N-dimethylacetamide 300mg, CremophorEL2.5mg, ethanol 2.1ml.Press body surface area 50-100mg/m during clinical independent use
2Administration is diluted quiet of back with 5% glucose or normal saline.
There is following problem in existing teniposide preparation in clinical use:
Anaphylaxis: contain a large amount of surfactant CremophorEL in the prescription, can cause histamine release in the body after the use, show as severe anaphylactic reaction.For this reason, the doctor must understand patient's allergies before doctor's advice, as whether to teniposide or Semen Ricini wet goods allergy; When clinical use, the medical worker needs close observation patient's situation, uses antihistamine drug to alleviate the severe allergic reaction that CremophorEL causes in case of necessity.The result should use very inconvenience clinically, brings very big misery to patient.
In recent years, the pharmacy worker is devoted to study the new drug-supplying system of minimizing or alternative CremophorEL use both at home and abroad, to improve curative effect of medication, reduces toxic and side effects.As be used for liposome, the cyclodextrin clathrate of whole body administration, for the microball preparation and the gel preparation of topical, microemulsion formulation for oral administration etc.New drug-supplying system does not all contain surfactant CremophorEL, therefore, can avoid anaphylactoid generation.But these novel formulation majorities still are in breadboard conceptual phase at present, also have instability as the liposome of drug administration by injection, easily leak, and the cost height is produced problems such as difficulty greatly.
Be to improve the safety of teniposide medication and the compliance of medication, we are to the novel form of teniposide: teniposide used for intravenous injection microemulsion formulation has carried out research all sidedly.The selected adjuvant of new recipe all is the intravenous injection level, particularly reduced the consumption of polyoxyethylene castor oil (CremophorEL) in the prescription significantly, by share with other surfactant, made more stable Emulsion, the moving experiment of rat body giving drugs into nose shows that novel form compares with VUMON , and both AUC are more or less the same.When guaranteeing that teniposide reaches drug effect concentration, eliminated the anaphylaxis that polyoxyethylene castor oil brings substantially, to solve the greatest problem that present teniposide injection exists.
Since the fifties, Emulsion transfusion was come out one after another, as the research of the drug-supplying system of carrier major progress has been arranged with Emulsion.Emulsion can increase the dissolubility and the stability of insoluble drug, and some drugs is made the Emulsion drug administration by injection can alleviate its zest and toxic and side effects.In recent years existing pastille Emulsion listing is as the Diprivan (propofol intravenous injection emulsion) of Astrazeneca AB's production; The nonsmall-cell lung cancer in late period of elemene intravenous injection emulsion treatment chemotherapy failure can make spirit after most patient, muscle power, sleep and appetite improve, and life quality improves; Oleum Fructus Bruceae Emulsion carries out that injection adds in the intravenous drip treatment in the body of prostate, advanced prostate cancer etc.Emulsion has low-viscosity, stablizes, absorbs characteristics such as rapid, and improves bioavailability of medicament, reduces toxic and side effects, clinical having a extensive future.Emulsion has following characteristics:
(1) as the refining Oleum Glycines of oil phase and nontoxic to human body, fully biodegradable and absorption in vivo as the phospholipid of emulsifying agent;
(2) big technology of producing solves;
(3) stable in properties;
(4) do not produce osmotic pressure behind the quiet notes above the human body standard.
Summary of the invention
The inventor is by studying intensively, invented a kind of intravenous injection microemulsion preparation of teniposide, can significantly reduce the consumption of CremophorEL in the existing teniposide injection,, provide safer teniposide injection to reduce the toxic and side effects that it is brought.Compare with existing teniposide injection, both AUC are equal substantially, and the anaphylaxis toxic and side effects obviously reduces, and patient's compliance obviously increases.
The present invention relates to teniposide with slightly solubility, oil for injection, part surface activating agent etc. is dissolved in the organic solvent, make the pre-emulsifying concentrated solution of teniposide, separately pre-emulsifying concentrated solution is added a kind of new teniposide used for intravenous injection microemulsion formulation that forms microemulsion in 5% glucose injection during clinical use, it is characterized in that in the preparation, teniposide or teniposide and paclitaxel, the mixture of etoposide is 0.05-5%, vegetable oil is 0.1-5%, emulsifying agent and co-emulsifier are 20-80%, organic solvent is 20-70%, and the ratio of above-mentioned supplementary material is weight percentage.Described emulsifying agent can be soybean lecithin, Ovum Gallus domesticus Flavus lecithin, Tween60, PluronicF68, CremophorEL, or their mixture.Described organic solvent is glycerol, dehydrated alcohol, propylene glycol, benzyl alcohol, N,N-dimethylacetamide, or their mixture.Described vegetable oil is Semen Maydis oil, soybean oil, Oleum sesami, safflower oil, or their mixture.
Preferred preparation is that the teniposide with effective dose joins in the ethanol of predetermined, adds required emulsifying agent that is soluble in organic solvent and oil for injection in said preparation, and packing is made this pre-emulsifying concentrated solution then.Before administration, pre-emulsifying concentrated solution is added in 5% glucose injection that contains emulsifying agent of dilution, form microemulsion.
The invention provides a kind of preparation technology of teniposide injection microemulsion, comprising:
Teniposide, oil for injection, surfactant, cosurfactant etc. are dissolved into fully dissolving in the organic solvent, obtain pre-emulsifying concentrated solution, resulting pre-emulsifying concentrated solution is faint yellow oily solution.
During clinical use, be in 5% the glucose solution, can obtain the teniposide microemulsion formulation for injection with the pre-emulsifying concentrated solution implantation concentration.When this microemulsion formulation uses, can adopt intravenous injection or the administration of intravenous drip mode.
Be excellent characteristic and the effect of checking teniposide microemulsion formulation for injection product of the present invention to be had, we have done following investigations to said preparation:
1. the mensuration of content of dispersion
Adopt high performance liquid chromatography to investigate the content of the teniposide in many groups teniposide microemulsion formulation for injection, the result shows: the content of the teniposide in the microemulsion formulation is the 95%-105% of labelled amount, shows that preparation of the present invention and preparation method have good homogeneity and industrial applicibility.
2. stability test
Investigated the influence of light, heat (40 ℃, 60 ℃), room temperature (25 ℃) and low temperature factors such as (2-8 ℃) to teniposide microemulsion formulation stability, the result shows: the teniposide microemulsion formulation is relatively more responsive to light and heat, need under low temperature (2-8 ℃) condition, preserve, can stablize 12 months.With room temperature accelerated test (40 ℃, RH75%) 3 months, every index had no significant change.
3. bioavailability test
In the bioavailability test, giving rat dosage respectively is teniposide microemulsion formulation or the commercially available injection product of teniposide of 9mg/kg, the result shows, the bioavailability of the teniposide microemulsion formulation of being developed is 86% of the commercially available injection product of teniposide, statistical test is not seen notable difference, and two preparations have bioequivalence.
4. acute irritation test
Laboratory animal: healthy guinea pig, male and female half and half, body weight 250-350g, 8 every group;
Be subjected to the reagent thing: 10% bovine serum albumin, injection volume is 0.5ml, as positive control; The blank solvent of teniposide injection, dosage are 2.5mg/kg; From the blank solvent of antigalactic, dosage is 2.5mg/kg; 5% glucose injection, injection volume 0.5ml is as negative control.Test and experimental result is marked and judged by pharmacological experiment teaching materials method.
Experimental result: serious acute anaphylactic reaction appears in the positive controls laboratory animal, as perpendicular hair, grab nose, cough, tremble, dyspnea etc.3 grades of acute anaphylactic reactions appear in the blank solvent group laboratory animal of teniposide injection, as repeatedly grabbing nose, repeatedly tremble, and sneeze, perpendicular hair is twitched, dyspnea, gatism appears in two routine animals; 1 order reaction occurs from antigalactic blank solvent group laboratory animal, perpendicular hair occurs as part; The reaction that is negative of glucose injection group laboratory animal.
Conclusion: according to Cavia porcellus anaphylaxis progression standard, the order of reaction reaches when (comprising 2 grades) more than 2 grades, judges that this test sample anaphylaxis test is positive.Injected dose is the blank solvent of the teniposide injection of 2.5mg/kg, and laboratory animal is positive; Injected dose is the self-control microemulsion blank solvent of 2.5mg/kg, the laboratory animal reaction that is negative.This result shows that owing to significantly reduced the consumption of CremophorEL in the former preparation, the acute irritation of self-control microemulsion blank solvent is starkly lower than the blank solvent of teniposide injection.
The following examples are that the present invention is further specified and explains, rather than the present invention is carried out any restriction.
Embodiment 1
Prescription:
Teniposide 0.24g
Dehydrated alcohol 6.4g
Lecithin 4.5g
Soybean oil 0.64g
CremophorEL 6.32g
5% glucose solution 500ml
Method for making:
Teniposide 0.24g is dissolved in the dehydrated alcohol of 6.4g, adds lecithin 4.5g, soybean oil 0.64g and CremophorEL6.32g again, make their mix homogeneously form pre-concentration liquid.It is in 5% the glucose solution that pre-concentration liquid is added 500ml concentration, jolts, and forms microemulsion.
Embodiment 2
Prescription:
Teniposide 0.24g
Dehydrated alcohol 8g
Lecithin 4g
Semen Maydis oil 0.8g
CremophorEL 8g
5% glucose solution 500ml
Method for making:
Teniposide 0.24g, dehydrated alcohol 8g, lecithin 4g, soybean oil 0.8g and CremophorEL8g mix homogeneously are formed pre-concentration liquid.It is in 5% the glucose solution that pre-concentration liquid is added 500ml concentration, jolts, and forms microemulsion.
Embodiment 3
Prescription:
Teniposide 0.24g
Lecithin 10g
Soybean oil 1.1g
Cremophor?EL 6.4g
Dehydrated alcohol 24g
5% glucose solution 500ml
Method for making:
Teniposide 0.24g and lecithin 10g, soybean oil 1.1g, Cremophor EL 6.4g and dehydrated alcohol 24g mix homogeneously are formed pre-concentration liquid.During the preparation emulsion pre-concentration liquid being injected 500ml concentration is 5% glucose injection, forms microemulsion.
Embodiment 4
Prescription:
Teniposide 0.24g
N,N-dimethylacetamide 2g
Dehydrated alcohol 5g
Lecithin 4g
Semen Maydis oil 0.8g
CremophorEL 8g
5% glucose solution 500ml
Method for making:
Teniposide 0.24g, N,N-dimethylacetamide, dehydrated alcohol 8g, lecithin 4g, soybean oil 0.8g and CremophorEL8g mix homogeneously are formed pre-concentration liquid.It is in 5% the glucose solution that pre-concentration liquid is added 500ml concentration, jolts, and forms microemulsion.
Embodiment 5
Prescription:
Teniposide 0.24g
Paclitaxel 0.3g
Dehydrated alcohol 5g
Lecithin 5g
Semen Maydis oil 1g
CremophorEL 10g
5% glucose solution 500ml
Method for making:
Teniposide 0.24g, paclitaxel 0.3g, dehydrated alcohol 5g, lecithin 5g, soybean oil 1g and CremophorEL10g mix homogeneously are formed pre-concentration liquid.It is in 5% the glucose solution that pre-concentration liquid is added 500ml concentration, jolts, and forms microemulsion.
Embodiment 6
Prescription:
Teniposide 0.24g
Etoposide 0.3g
Dehydrated alcohol 5g
Lecithin 5g
Semen Maydis oil 1g
CremophorEL 10g
5% glucose solution 500ml
Method for making:
Teniposide 0.24g, etoposide 0.3g, dehydrated alcohol 5g, lecithin 5g, soybean oil 1g and CremophorEL10g mix homogeneously are formed pre-concentration liquid.It is in 5% the glucose solution that pre-concentration liquid is added 500ml concentration, jolts, and forms microemulsion.
Be appreciated that those skilled in the art can add other pharmacy acceptable auxiliary separately or together in the active component of preparation of the present invention and adjuvant or the ratio of each component carried out minor alteration and do not influence the fundamental property of pharmaceutical preparation.But the pharmaceutical preparation and the preparation method that are obtained by these changes all do not break away from spirit of the present invention, drop in the protection domain of description of the present invention and claims yet.
Claims (12)
1, a kind of teniposide used for intravenous injection Emulsion is characterized in that following medicine is a raw material: teniposide, vegetable oil, emulsifying agent, organic solvent.
2,, it is characterized in that described medicine can be the mixture of teniposide or teniposide and paclitaxel, etoposide according to the teniposide used for intravenous injection Emulsion of claim 1.
3,, it is characterized in that described emulsifying agent can be soybean lecithin, Ovum Gallus domesticus Flavus lecithin, Tween 60, Pluronic F68, Cremophor EL or their mixture according to the teniposide used for intravenous injection Emulsion of claim 1.
4, according to the teniposide used for intravenous injection Emulsion of claim 1, it is characterized in that described organic solvent is glycerol, dehydrated alcohol, propylene glycol, benzyl alcohol, N,N-dimethylacetamide, or their mixture.
5, according to the teniposide used for intravenous injection Emulsion of claim 1, it is characterized in that described vegetable oil is Semen Maydis oil, soybean oil, Oleum sesami, safflower oil, or their mixture.
6, according to the teniposide used for intravenous injection Emulsion of claim 1, it is characterized in that teniposide is dissolved in vegetable oil, emulsifying agent is in the pre-emulsifying concentrated solution that organic solvent is formed.
7,, but it is characterized in that implantation concentration is the Emulsion of 5% the automatic emulsified formation homogeneous of glucose injection according to the teniposide used for intravenous injection Emulsion pre-emulsifying concentrated solution of claim 1.
8, according to the mean diameter size of the teniposide used for intravenous injection Emulsion of claim 1 in the 10-10000nm scope.
9,, it is characterized in that described medicine accounts for the prescription weight percentage ranges at 0.05-5% according to the teniposide used for intravenous injection Emulsion of claim 2.
10,, it is characterized in that described emulsifying agent accounts for the prescription weight percentage ranges at 20-80% according to the teniposide used for intravenous injection Emulsion of claim 3.
11,, it is characterized in that described organic solvent accounts for the prescription weight percentage ranges at 20-70% according to the teniposide used for intravenous injection Emulsion of claim 4.
12,, it is characterized in that described vegetable oil accounts for the prescription weight percentage ranges at 0.1-5% according to the teniposide used for intravenous injection Emulsion of claim 5.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2006101676888A CN101015563A (en) | 2006-12-22 | 2006-12-22 | Intravenous injection microemulsion preparation of teniposide |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2006101676888A CN101015563A (en) | 2006-12-22 | 2006-12-22 | Intravenous injection microemulsion preparation of teniposide |
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| Publication Number | Publication Date |
|---|---|
| CN101015563A true CN101015563A (en) | 2007-08-15 |
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| CNA2006101676888A Pending CN101015563A (en) | 2006-12-22 | 2006-12-22 | Intravenous injection microemulsion preparation of teniposide |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101829052A (en) * | 2010-03-16 | 2010-09-15 | 王国强 | Self-emulsifying preparation of taxane compound and preparation method thereof |
| CN101912362A (en) * | 2010-09-01 | 2010-12-15 | 北京大学 | Fat emulsion pre-emulsifying concentrated solution for teniposide intravenous injection and preparation method thereof |
| CN102228431A (en) * | 2010-03-16 | 2011-11-02 | 王国强 | Self-emulsified medicinal composition for taxane compounds |
| CN106137943A (en) * | 2015-04-01 | 2016-11-23 | 中国人民解放军第二军医大学 | A kind of teniposide intravenous administration formulation and preparation method thereof |
-
2006
- 2006-12-22 CN CNA2006101676888A patent/CN101015563A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101829052A (en) * | 2010-03-16 | 2010-09-15 | 王国强 | Self-emulsifying preparation of taxane compound and preparation method thereof |
| CN102228431A (en) * | 2010-03-16 | 2011-11-02 | 王国强 | Self-emulsified medicinal composition for taxane compounds |
| CN101829052B (en) * | 2010-03-16 | 2011-12-14 | 王国强 | Self-emulsifying preparation of taxane compound and preparation method thereof |
| CN101912362A (en) * | 2010-09-01 | 2010-12-15 | 北京大学 | Fat emulsion pre-emulsifying concentrated solution for teniposide intravenous injection and preparation method thereof |
| CN106137943A (en) * | 2015-04-01 | 2016-11-23 | 中国人民解放军第二军医大学 | A kind of teniposide intravenous administration formulation and preparation method thereof |
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Open date: 20070815 |