CN102085184A - Preparation of fotemustine fat emulsion for injection - Google Patents
Preparation of fotemustine fat emulsion for injection Download PDFInfo
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- CN102085184A CN102085184A CN2009102315594A CN200910231559A CN102085184A CN 102085184 A CN102085184 A CN 102085184A CN 2009102315594 A CN2009102315594 A CN 2009102315594A CN 200910231559 A CN200910231559 A CN 200910231559A CN 102085184 A CN102085184 A CN 102085184A
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Abstract
The invention relates to a preparation method for a fotemustine fat emulsion injection. The invention comprises the following steps: putting soybean oil, mid-chain oil, and oleic acid into a container, stirring the mixture to prepare an oil phase; adding a certain amount of water into a mixture of fotemustine, soybean phosphatide, and glycerin to prepare a water phase; adding the oil phase into the water phase, stirring uniformly, performing high-speed shearing, adjusting the pH to be neutral, homogenizing the mixture by a high-pressure homogenizer to prepare a drug-loaded fat emulsion, filtering, filling into an ampoule, injecting nitrogen, performing melt sealing and autoclaving. The injection emulsion of the invention has the advantages of high efficiency, large drug loading amount, no toxic and side effects, good stability, and convenient usage, and the preparation method is rapid and simple, and is applicable to large amount preparation and industrial production.
Description
Technical field
The present invention relates to a kind of fotemustine fat emulsion injection and preparation method thereof, belong to the medical biotechnology field.
Background technology
Glioblastoma is common brain tumor, and main Therapeutic Method is operation and postoperation radiotherapy, and chemotherapy is never paid attention to fully.Its main cause is that most of chemotherapeutics can not be difficult to bring into play tumor-inhibiting action by blood brain barrier.Because glioma is infiltrative growth, unclear with the normal cerebral tissue boundary, operation is excision thoroughly, and the postoperative recurrence rate is high, the treatment of glioblastoma surgery alone, and only 6 months mean survival time (MST),, the postoperative combined with chemotherapy is the important means of current treatment glioma
When the patient who suffers from tumor is carried out chemotherapy and radiation; usually can cause the digestive system untoward reaction during malignant tumor chemotherapy; mainly show as loss of appetite, feel sick, vomiting, mucositis, stomachache and diarrhoea etc.; these untoward reaction hinder the smooth implementation of chemotherapy and the raising of drug dose, go back entail dangers to life when serious.When carrying out partner treatment with some antitumor drug, the nausea and vomiting phenomenon that chemotherapy causes directly influences the oral administration efficient of antitumor drug, and compliance of patients is also very poor.Therefore drug administration by injection is necessary for the patient of chemotherapy.Clinical research shows that the fotemustine intravenous chemotherapy is effective and safe for glioblastoma, thereby is listed in a kind of medicine of cerebral tumor chemotherapy first-selection.Fotemustine is the nitrosoureas medicine, has higher fat-solublely, is easy to by blood brain barrier, to all toxic effect of each phase of tumor cell.Fotemustine is the antimitotic cytostatics of nitrosoureas; have alkanisation and carbamyl turns usefulness into, zoopery shows that it has broad-spectrum anti-tumor activity, and its mechanism of action mainly is by suppressing dna replication dna; the killing tumor cell circle, thereby higher anti-tumor activity is arranged.Yet this medicine uses aseptic ethanol to do solvent at its injectable powder of clinical practice at present, the dissolving fotemustine, and then fotemustine solution added 5% glucose solution 250mL, do intravenous drip.The method with an organic solvent dehydrated alcohol is done solvent, and toxicity is big.Therefore the present invention relates to develop intravenous injection fotemustine lipomul, substitute dehydrated alcohol, and can be directly used in intravenous drip during clinical use, easy to use.
The intravenous injection fatty breast is a development in recent years novel pharmaceutical formulation faster, has very high clinical and economic worth.Fat milk is the stable O/W type Emulsion made from vegetable oil, phospholipid emulsifier, isotonic agent and water for injection, but injection for intravenous can also have application simultaneously fully by organism metabolism and utilization on other dosage form.The safety of fat milk is good, and is non-stimulated to vein, can provide high-energy fast for the patient, become the important preparation research direction that improves curative effect of medication.For a long time, lipomul is used for clinical mainly as a kind of concentrated high-energy parenteral nutrition liquid, for not taking food and the patient of famine nutrition provides heat energy and essential fatty acid, and can be fully by organism metabolism and utilization.Most of tumor patient need supplement the nutrients simultaneously in drug application, and fat milk can be the patient institute's energy requirement is provided, and therefore fotemustine is made the injection fat milk and provided certain nutritional labeling for the patient in the treatment cerebral tumor.
Summary of the invention
The object of the invention provides a kind of stable fotemustine fat emulsion for injection, and preparation method is provided.In treatment cerebral tumor disease, for the patient supplements the nutrients.The technical problem to be solved in the present invention is that fotemustine is made the lipomul with suitable pH value, has good stable to guarantee the stability of medicine and Emulsion, to make the lipomul that makes, and reduces the side reaction of medicine, improves curative effect.
The present invention is achieved by the following technical solutions:
A kind of fotemustine fat emulsion injection, comprise following component: fotemustine, oil for injection, emulsifying agent, stabilizing agent, isoosmotic adjusting agent and water, wherein, each component concentrations is: fotemustine 0.5～10mg/ml, oil for injection 4～30g/ml, emulsifying agent 0.6～3.0g/ml, stabilizing agent 0.1～3.0g/ml, isoosmotic adjusting agent 2～4g/ml.
Described fatty acid injection also comprises the pH regulator agent, and it is used to regulate pH to 5.0～9.0.Character is white emulsion drop, and breast grain particle diameter is 100～500nm.
A kind of preparation method of fotemustine fat emulsion injection may further comprise the steps:
(1) with soybean oil, midchain oil, oleic acid are put in the container, stir, and make oil phase;
(2) with fotemustine, soybean lecithin, glycerol and suitable quantity of water join in the container, stir, and make water;
(3) oil phase that step (1) is obtained is under agitation poured the aqueous phase that step (2) obtains into, and high speed shear is made colostrum; Transfer to neutrality with sodium hydroxide; Colostrum is moved into the high pressure dispersing emulsification machine, homogenize 5～30 times;
(4) with after the filtration of fat milk Emulsion, fill is led to nitrogen, sealing by fusing, autoclaving in ampoule.Temperature is 100～121 ℃, and the time is 10～30min.
The present invention makes oil and the mixed uniformly lipomul of water energy with fotemustine, its quality outward appearance homogeneous after testing, mean diameter is about 100～500nm, pH5.0～9.0, can use for injection, preparation method is simple, and prepared fotemustine fat emulsion injection has remarkable antitumor effect, according to general lipomul characteristics, antitumor drug fotemustine lipomul of the present invention also has slow release, targeting, effects such as energy is provided for body.
Utilizing the fotemustine infatmul agent of this technology preparation is a kind of oil-in-water emulsion, and it does not contain organic solvent, and is less to blood vessel irritation, thereby has alleviated irritative response, and haemolysis, allergic side reactions, strengthens patient's compliance; And have targeting and a certain lymph affinity.In addition, the fotemustine infatmul stable in properties of preparation can high pressure resistant disinfecting action.Simultaneously, also have following advantage: this product preparation process advanced person, reliable, Emulsion particle diameter are at 100～500nm, and drug loading is bigger, has possessed to enlarge the condition and the technology of producing, easier realization commercialization; The long-term clinical practice experience is arranged, easily accepted by clinical; Need not harsh storing condition, easy to use.
The specific embodiment
The invention will be further described below in conjunction with embodiment, but the present invention does not limit in these embodiments.
Embodiment 1
The fotemustine lipomul, it consists of:
Fotemustine 50mg
Injection soybean oil 10g
Midchain oil 10g
Oleic acid 1.0g
Soybean phospholipid 1.0g
Glycerol 2.0g
Water for injection adds to 100ml
The preparation method of above-mentioned lipomul:
Take by weighing oil phase by recipe quantity and stir, take by weighing the fotemustine of recipe quantity, injection soybean phospholipid and glycerol and an amount of water mix makes it to be dissolved as fully water, and oil phase is joined aqueous phase under stirring, and high speed shear gets colostrum; Transferring pH is 6.0～8.0, even 20 times of 100mpa breast, and emulsion in ampoule, is put the 20min that sterilizes under 121 ℃ of conditions with the Emulsion embedding with 0.45 μ m filtering with microporous membrane, both.Particle diameter is between 100～500nm.
2 one kinds of fotemustine lipomuls of embodiment, composed of the following components:
Fotemustine 200mg
Oleum Arachidis hypogaeae semen 5g
Lecithin 1.2g
Cholic acid 1.0g
Propylene glycol 0.5g
Water adds to 100ml
Take by weighing oil phase by recipe quantity and stir, take by weighing the water that recipe quantity contains the medicine fotemustine, oil phase is joined aqueous phase under stirring, high speed shear gets colostrum; Transferring pH is 6.0～8.0, even 20 times of 100mpa breast, and emulsion in ampoule, is put the 20min that sterilizes under 121 ℃ of conditions with the Emulsion embedding with 0.45 μ m filtering with microporous membrane, both.Particle diameter is between 100～500nm.
3 one kinds of fotemustine lipomuls of embodiment, composed of the following components:
Fotemustine 500mg
Oleum Sesami 20g
Poloxamer 2g
Cholesterol 4g
Polyethylene Glycol 15g
Water adds to 100ml
Take by weighing oil phase by recipe quantity and stir, take by weighing the water that recipe quantity contains the medicine fotemustine, oil phase is joined aqueous phase under stirring, high speed shear gets colostrum; Transferring pH is 6.0～8.0, even 20 times of 100mpa breast, and emulsion in ampoule, is put the 20min that sterilizes under 121 ℃ of conditions with the Emulsion embedding with 0.45 μ m filtering with microporous membrane, both.Particle diameter is between 100～500nm.
4 one kinds of fotemustine lipomuls of embodiment, composed of the following components:
Fotemustine 1000mg
Safflower oil 30g
Glycerin mono-fatty acid ester 5g
Enuatrol 2g
Sorbitol 10g
Water adds to 100ml
Take by weighing oil phase by recipe quantity and stir, take by weighing the water that recipe quantity contains the medicine fotemustine, oil phase is joined aqueous phase under stirring, high speed shear gets colostrum; Transferring pH is 6.0～8.0, even 20 times of 100mpa breast, and emulsion in ampoule, is put the 20min that sterilizes under 121 ℃ of conditions with the Emulsion embedding with 0.45 μ m filtering with microporous membrane, both.Particle diameter is between 100～500nm.
The result: the fotemustine fat milk of the present invention's preparation is more stable.
Claims (5)
1. a fotemustine fat milk injection wherein contains the active component fotemustine.
2. antitumor drug fotemustine fat milk injection as claimed in claim 1 is characterized in that this lipomul by active component fotemustine, oil for injection, and injection phospholipid and water for injection are formed.Described injection vegetable oil is selected from soybean oil, Oleum Arachidis hypogaeae semen, Oleum Sesami, safflower oil, Oleum Gossypii semen, Semen Maydis oil, safranine caul-fat, the mixture of a kind of or any two kinds or the two kinds later arbitrary proportions in Oleum Ricini and the Oleum helianthi etc.; Described emulsifying agent is selected from soybean phospholipid, egg yolk lecithin, poloxamer, glycerin mono-fatty acid ester, the mixture of one or more in tween 80 or the polyoxyethylene castor oil; Described grade is oozed and is adjusted agent and be selected from glycerol, propylene glycol, and Polyethylene Glycol, sorbitol, xylitol, the mixture of one or more in glucose or the sodium chloride is adjusted to body fluid etc. and oozes; Described stabilizing agent is selected from oleic acid, enuatrol, the mixture of one or more in cholic acid or the sodium cholate.
3. a kind of antitumor drug fotemustine lipomul as claimed in claim 1 is characterized in that the preferred soybean oil of described vegetable oil, the preferred soybean phospholipid of emulsifying agent, osmotic pressure regulator preferably glycerine.
4. the preparation method of a fotemustine lipomul comprises the following steps:
(1) with soybean oil, midchain oil, oleic acid are put in the container, stir, and make oil phase;
(2) with fotemustine, soybean lecithin, glycerol and suitable quantity of water join in the container, stir, and make water;
(3) oil phase that step (1) is obtained is under agitation poured the aqueous phase that step (2) obtains into, and high speed shear is made colostrum; Transfer to neutrality with sodium hydroxide; Colostrum is moved into high pressure dispersing emulsification machine, homogenize;
(4) with after the filtration of fat milk Emulsion, fill is led to nitrogen, sealing by fusing, autoclaving in ampoule.
5. the preparation method of fotemustine fat milk injection according to claim 1 is characterized in that comprising the steps:
(1) Zhi Bei fat milk is transferred pH scope 5.0～9.0 with sodium hydroxide.
(2) the medicine carrying fat milk is 5～30 times with the even number of times of high pressure homogenization machine high pressure breast.
(3) the medicine carrying fat milk of preparation adopts autoclaving, and temperature is 100～121 ℃, and the time is 10～30min.
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| CN2009102315594A CN102085184A (en) | 2009-12-04 | 2009-12-04 | Preparation of fotemustine fat emulsion for injection |
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| CN2009102315594A CN102085184A (en) | 2009-12-04 | 2009-12-04 | Preparation of fotemustine fat emulsion for injection |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114129519A (en) * | 2021-10-18 | 2022-03-04 | 湖北一半天制药有限公司 | Docetaxel nano fat emulsion injection and preparation method thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114129519A (en) * | 2021-10-18 | 2022-03-04 | 湖北一半天制药有限公司 | Docetaxel nano fat emulsion injection and preparation method thereof |
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Application publication date: 20110608 |