CN102895187B - Preparation of benflumetol fat emulsion for injection and application of benflumetol fat emulsion in treatment of malaria - Google Patents
Preparation of benflumetol fat emulsion for injection and application of benflumetol fat emulsion in treatment of malaria Download PDFInfo
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Abstract
The invention discloses a benflumetol fat emulsion injection preparation which contains 0.03 to 35 wt% of benflumetol, 10.0 to 30.0 wt% of oil for injection, 0.6 to 30.0 wt% of an emulsifier, 0 to 10 wt% of a solubilizer, 0 to 5 wt% of a co-emulsifier, 2.25 to 7 wt% of an isotonic agent and 0.002 to 0.075 wt% of an anti-oxidant, with the balance being injection water. The invention also discloses a preparation method and pharmacodynamic and safety evaluation for the benflumetol fat emulsion injection preparation. The benflumetol fat emulsion provided by the invention has the characteristics of good biocompatibility, high physical stability, convenient preparation, good security, high drug loading capacity and the like, has a particle size of less than 200 mu m and is suitable for injection, e.g, intravenous injection and intramuscular injection. According to the invention, the characteristic that a soybean oil fat emulsion inhibits growth of plasmodium falciparum is utilized to enhance anti-malarial effects of drugs, to improve bioavailability of the drugs and to reduce toxic and side effects of the drugs; nutrients needed by the body of a patient with malaria can be provided, the activity of lymphocytes of the patient is improved, which assists the patient in resisting malaria and recovering.
Description
Technical field
The invention belongs to pharmaceutical field, relate to a kind of fat milk injection, particularly a kind of benflumetol fat milk injection and preparation method thereof.
Background technology
Arteannuin is Chinese scholar at the early 1970s effective malaria monomer of one that goes out of separating-purifying from Herba Artemisiae Annuae, it is the sesquiterpene lactone compound containing peroxide bridge structure, have fast, efficient, without Drug resistance, hypotoxic feature, be called " the maximum hope for the treatment of malaria " by World Health Organization (WHO), can be considered that China pharmacy worker is to the maximum contribution of human society.Its discovery becomes world's malaria history another important mileage after quinine.But research shows, takes separately Arteannuin preparation for a long time and easily makes protozoon develop immunity to drugs, and is combined with other malaria medicine by arteannuin and make compound formulation, also can have the curative effect of nearly 95% to the malaria of non-concurrent type.Therefore, in February, 2004, WHO reforms malaria treatment medication policy, proposes to stop using artemisine folk prescription antimalarial drug, and advocate the combination medicine (Artemisinin-based combination therapies is called for short ACTs therapy) adopted based on artemisinin-based drug.At present, this combination medicine based on artemisinin-based drug mainly contains: Artemether-LUMEFANTRINE, artesunate-amodiaquine, artesunate-sulfamethoxine-pyrimethamine, artesunate-mefloquine, amodiaquine and sulfamethoxine-pyrimethamine drug combination etc., the effect of wherein Artemether-LUMEFANTRINE drug combination is best.This is because Artemether-LUMEFANTRINE drug combination can potentiation complementary: artemisinin derivatives Artemether has stronger killing action to Plasmodium merozoite, for multiple resistant malaria and anti-Chloroquine-resistant Falciparum Malaria disease evident in efficacy.But it is short to there is again action time in it, the shortcomings such as relapse rate is high.It is totally thorough that benflumetol kills plasmodium, and effective percentage reaches more than 95%, and relapse rate is lower than 5%, but onset is slow.So will can overcome the shortcoming that Artemether relapse rate is high and benflumetol effect is slow behind two recurrence due to taking drug sides simultaneously.Have control symptom fast, kill plasmodium thoroughly, the strain of antagonism worm effectively, delay advantages such as developing immunity to drugs.Further, this compound recipe and other antimalarial existing are without cross tolerance, easy to use, safe.This compound oral tablet has obtained the listing approval of U.S. FDA on April 8th, 2009.But at present, the combined dosage form of Artemether and benflumetol only has oral formulations, as " number of patent application is the Chinese patent of 90106722.9 " discloses Artemether/benflumetol compound oral tablet, compound oral syrup, compound suppository etc." number of patent application is the Chinese patent of 200610037383.5 " discloses the self-emulsifier of Artemether/benflumetol compound recipe." number of patent application is the Chinese patent of 200710057537.1 " discloses the drop pill of Artemether/benflumetol compound recipe." number of patent application be 200710057538.6 Chinese patent disclose a kind of preparation method for the treatment of the benflumetol dripping pill of malaria ".These are all peroral dosage forms, the emergency treatment of malaria can not be used for when Clinical practice, although they are at the oral administration biaavailability that improve benflumetol in varying degrees simultaneously, but due to the fatty dependency of benflumetol, (namely the oral absorption of benflumetol is by the impact of food, eat food rich in fat during patient on medication, higher drug absorption rate and higher blood drug level just can be had to kill malaria worm) make benflumetol when oral, need increase taking dose and number of times to ensure the clinical therapeutic efficacy of medicine.So benflumetol dosage when Clinical practice, up to 1840mg, even reaches 2880mg, and taking of such long-term high dose can accelerate drug-fast generation, thus greatly shortens the service life of benflumetol, reduce result of use.In addition from the angle of patient, high dose, frequently take medicine and increase financial burden undoubtedly, in fact, costly become the main barrier of malaria patients' treatment at present.In order to overcome above-mentioned defect, be necessary the novel form developing benflumetol.
Fat milk injection is a kind of new fat-soluble medicine carrier.It take soybean oil as main component, and be emulsifying agent with refined lecithin, glycerol is isotonic agent, forms through high pressure homogenize.It has good biocompatibility, physical stability high, be convenient to preparation, the characteristic such as safety is good, drug loading is high, be very suitable for injection.Meanwhile, it can also improve the lymphocyte activity of malnourished patient, for patient provides nutrition, is highly suitable for the emergency treatment of subtertian malaria and general malaria.
In sum, in order to protect the Clinical practice life-span of benflumetol, improve the bioavailability of benflumetol, the present invention discloses a kind of injection and preparation method of benflumetol fat milk.
Summary of the invention
In order to improve the bioavailability of benflumetol, meeting the demand of the pernicious treatment malaria of clinical treatment for injecting, the invention provides a kind of benflumetol injection and benflumetol lipomul.
Owing to being injection, so its bioavailability is 100%.It is without the need to adding any cosolvent when for injecting, and because this reducing the incidence rate of toxic and side effects, and it can also provide nutrition needed for health for malaria patients, improves the lymphocyte activity of patient, contributes to patient and resist malaria and rehabilitation.
Benflumetol fat milk injection of the present invention, be processed into by following composition:
All the other are water for injection.
Wherein, described oil for injection is soybean oil, Oleum Camelliae, Oleum Sesami, middle long-chain fatty acid ester, olive oil, Oleum Curcumae, pearl barley oil, Oleum Bulbus Allii, safflower oil, Fructus Zanthoxyli oil, Rhizoma Chuanxiong oil, Herba Artemisiae Annuae oil, Oleum Hippophae, wintergreen oil, Radix Oenotherae erythrosepalae oil, Radix Angelicae Sinensis oil, oil of Rhizoma Zingiberis Recens, Herba Schizonepetae oil, Fructus Forsythiae oil, eucalyptus oil, perilla oil, Oleum Citri Reticulatae, Oleum Viticis Negundo, Oleum Rosae Rugosae, Oleum Ricini, Oleum menthae, oil of Herba Artemisiae Scopariae, fennel oil, pine oil, Oleum Caryophylli, Oleum Anisi Stellati, Oleum thymi vulgaris, Oleum Cinnamomi, Oleum Folium Artemisiae Argyi, Fructus Perillae oil, turmeric oil, Cortex Melaleucae leucadendrae oil, Essential lavender oil, Radix Aucklandiae oil, patchouli oil, Herba Verbenae oil, Common Wormwood oil, Salvia Sclare L.oil, Rhizoma Atractylodis oil, Myrtus communis oil, Fructus Citri Limoniae oil, Fructus Aurantii Immaturus oil, Oleum Ocimi Gratissimi, Folium Perillae oil, art (pine) pomegranate oil, Oleum Cocois, Fructus Amomi oil, olive oil, citronella oil, Oleum Pelargonii Graveolentis, Herba Moslae oil, Oleum Menthae Rotundifoliae, Du Shan oil, Herba Pogostemonis oil, Storax oil, oil of Ribes nigrum L., Fructus Schisandrae oil, Rhizoma Acori Graminei oil, Fructus Cnidii oil, Fructus Phellodendri oil, Oleum lavandula angustifolia, oil of rosemary, oleum bergamottae, sandal oil, Fructus Dauci Sativae oil, Cacumen Cupressi oil, seed oil of Herba Apii graveolentis, Herba Origani oil, citronellal oil, Fructus Coriandri oil, orange blossom oil, Semen Myristicae oil, oil of Bulbus Allii Cepae, Oleum Santali albi, Flos Tagetis Erectae oil, thyme oil, any one or more mixture in Cananga odorata oil.
Wherein, described emulsifying agent is any one in Ovum Gallus domesticus Flavus lecithin, soybean lecithin, hydrogenated yolk lecithin, hydrogenated soy phosphatidyl choline, synthetic lecithin;
Wherein, described co-emulsifier be in Tween 80, F68, enuatrol, potassium oleate, oleic acid any one or appoint several;
Wherein, described solubilizing agent is any one of dehydrated alcohol, chloroform, acetone or isopropyl alcohol;
Wherein, described isotonic agent is any one of glycerol, glucose or xylitol.
Wherein, described antioxidant is vitamin E.
Present invention also offers the preparation method of benflumetol fat milk injection, comprise the following steps:
Step 1: the solubilizing agent that the benflumetol of 0.03 ~ 35wt% puts into 0 ~ 10wt% dissolved, then mix with the oil for injection of 10.0 ~ 30.0wt%, evaporates 10 ~ 120min and removes solubilizing agent in 80 DEG C of water-baths; Add the emulsifying agent of 0.6 ~ 30.0wt% and the antioxidant of 0.002 ~ 0.075wt% under nitrogen protection, be heated to 40 ~ 80 DEG C and obtain forming oil mixture;
Step 2: the isotonic agent of 2.25 ~ 7wt%, the co-emulsifier of 0 ~ 5wt% and water for injection are mixed at 40 ~ 80 DEG C, forms aqueous mixture;
Step 3: the oil mixture that aqueous mixture step 2 obtained under nitrogen protection and step 1 obtain mixes, then at 40 ~ 80 DEG C, under 5000 ~ 12000r/min condition after high speed dispersion 5 ~ 30min, mechanical agitation 60 ~ 120min again, pH to 6.0 ~ 9.0 are regulated with 0.1mol/L NaOH or HCL, under pressure is 90 ~ 110MPa condition, carry out homogenizing 6 ~ 9 times, obtain uniform milky solution;
Step 4: step 3 gained milky solution is filtered, leads to nitrogen-sealed, through 100 ~ 125 DEG C of sterilization treatment 15 ~ 50min or after 0.22 μm of sterilised membrane filter filters, less than 25 DEG C storages.
Present invention also offers the application of benflumetol fat milk injection in treatment malaria.This pharmaceutical dosage form can be intramuscular injection or intravenous injection.Detect (referring to 5.1) according to antimalarial active in body, respectively organize the inoculation of mouse peritoneal quantification during experiment containing l × 10
7individual by the erythrocyte of Mus plasmodium parasitism, inoculum concentration 0.2ml/ only.After inoculation, second day is by group administration, the 4d inhibition test method(s) specified by WHO, successive administration 3 days.Benflumetol fat milk administration group (concentration is respectively 90,45,22.5 mg/kg/d), tail drug administration by injection.The negative conversion rate that result shows each benflumetol fat milk injection administration group mice is 100%, illustrates that benflumetol fat milk has good antimalarial active, may be used for malaria treatment.
The bioavailability of benflumetol is brought up to 100% by benflumetol fat milk injection prepared by the inventive method.Further, fat milk can be utilized to suppress the characteristic of growth of malaria parasites, nutrition supply, strengthen the antimalarial effect of benflumetol, simultaneously for malaria patients provide the nutrition needed for health, improve the lymphocyte activity of patient, contribute to patient and resist malaria and rehabilitation.Benflumetol fat milk injection prepared by the inventive method can be directly used in injection, no longer needs hydrotropy carrier, thus reduces the toxic and side effects to human body, can increase the stability of medicine simultaneously.
Accompanying drawing explanation
Fig. 1: containing plasmodium (Figure 1A) and the microphotograph not containing plasmodium (Figure 1B) after turning out cloudy in mouse blood
Detailed description of the invention
The amount ranges of the present invention to adjuvant various in the pharmaceutical formulation of injection benflumetol fat milk is verified.Below in conjunction with embodiment, the present invention is elaborated, but be not limited only to following Examples.
One, the benflumetol lipomul injection prepared of different oil phase
Embodiment 1:
Prescription:
30mg benflumetol is put into 2mL acetone and is fully dissolved into solution; this solution is mixed with 10g injection soybean oil; add the antioxidant vitamin E of 1.2g injection Ovum Gallus domesticus Flavus lecithin, 0.02g after evaporation removing acetone under nitrogen protection, in 60 DEG C of mixing, form oil mixture.By 50mL water for injection, 0.4g enuatrol and 2.5g glycerol in 60 DEG C of mixing, form aqueous mixture.Under nitrogen protection aqueous mixture is mixed with oil mixture, and add water to 100mL, at 60 DEG C, after 6500r/min high speed dispersion, mechanical agitation 20min makes colostrum, after regulating pH to 7.0, under pressure is 105MPa condition, homogenizing 8 times, obtains uniform milky solution; Above-mentioned milky solution filters, logical nitrogen-sealed, after 115 DEG C of sterilization treatment 15min, and less than 25 DEG C storages.
Embodiment 2:
Prescription:
500mg benflumetol is put into 4mL chloroform and is fully dissolved into solution; this solution is mixed with 10g injection Oleum Camelliae; add the antioxidant vitamin E of 1.2g injection lecithin, 0.02g after evaporation removing chloroform under nitrogen protection, in 70 DEG C of mixing, form oil mixture.By 70mL water for injection, 2.5g xylitol, 0.2g F68 in 70 DEG C of mixing, form aqueous mixture.Under nitrogen protection aqueous mixture is mixed with oil mixture, add water to 100mL, at 70 DEG C, after 7000r/min high speed dispersion, mechanical agitation 20min makes colostrum, after regulating pH to 7.5, under pressure is 90MPa condition, carry out homogenizing 9 times, obtain uniform milky solution; Above-mentioned milky solution filters, logical nitrogen-sealed, after 120 DEG C of sterilization treatment 25min, and less than 25 DEG C storages.
Two, the benflumetol lipomul injection prepared of different emulsifiers
Embodiment 3:
Prescription:
300mg benflumetol is put into 6mL acetone and is fully dissolved into solution; this solution is mixed with 20g injection Oleum Sesami; add the antioxidant vitamin E of 2.4g injection Ovum Gallus domesticus Flavus lecithin, 0.02g after evaporation removing acetone under nitrogen protection, in 70 DEG C of mixing, form oil mixture.By 150mL water for injection, 5g glycerol, 0.02g oleic acid in 70 DEG C of mixing, form aqueous mixture.Under nitrogen protection aqueous mixture is mixed with oil mixture, add water to 200mL, at 70 DEG C, after 7500r/min high speed dispersion, mechanical agitation 20min makes colostrum, after regulating pH to 8.0, under pressure is 95MPa condition, carry out homogenizing 6 times, obtain uniform milky solution; Above-mentioned milky solution filters, logical nitrogen-sealed, after 125 DEG C of sterilization treatment 10min, and less than 25 DEG C storages.
Embodiment 4:
Prescription:
120mg benflumetol is put into 3mL isopropyl alcohol and is fully dissolved into solution; this solution is mixed with long-chain fatty acid ester in 30g injection; the antioxidant vitamin E of 1.2g injection hydrogenated yolk lecithin, 0.02g is added under nitrogen protection after evaporation removing isopropyl alcohol; in 60 DEG C of mixing, form oil mixture.By 50mL water for injection, 2.5g glycerol, 0.4g F68 in 70 DEG C of mixing, form aqueous mixture.Under nitrogen protection aqueous mixture is mixed with oil mixture, add water to 100mL, at 70 DEG C, after 8000r/min high speed dispersion, mechanical agitation 15min makes colostrum, after regulating pH to 8.0, under pressure is 100MPa condition, carry out homogenizing 8 times, obtain uniform milky solution; Above-mentioned milky solution filters, logical nitrogen-sealed, after 100 DEG C of sterilization treatment 30min, and less than 25 DEG C storages.
Three, the benflumetol lipomul injection prepared of different co-emulsifier
Embodiment 5:
Prescription:
400mg benflumetol is put into 4mL chloroform and is fully dissolved into solution; this solution is mixed with 200g injection soybean oil; add the antioxidant vitamin E of 12g injection lecithin, 0.15g after evaporation removing chloroform under nitrogen protection, in 60 DEG C of mixing, form oil mixture.By 900mL water for injection, 25g glycerol, 0.4g F68 in 60 DEG C of mixing, form aqueous mixture.Under nitrogen protection aqueous mixture is mixed with oil mixture, add water to 1000mL, at 60 DEG C, after 8900r/min high speed dispersion, mechanical agitation 15min makes colostrum, after regulating pH to 7.8, under pressure is 110MPa condition, carry out homogenizing 6 times, obtain uniform milky solution; Above-mentioned milky solution filters, logical nitrogen-sealed, after 125 DEG C of sterilization treatment 10min, and less than 25 DEG C storages.
Embodiment 6:
Prescription:
700mg benflumetol is put into 8mL chloroform and is fully dissolved into solution; this solution is mixed with 300g injection Oleum Camelliae; add the antioxidant vitamin E of 24g injection Ovum Gallus domesticus Flavus lecithin, 0.21g after evaporation removing chloroform under nitrogen protection, in 70 DEG C of mixing, form oil mixture.By 900mL water for injection, 25g glycerol, 0.04g oleic acid in 70 DEG C of mixing, form aqueous mixture.Under nitrogen protection aqueous mixture is mixed with oil mixture, add water to 1000mL, at 70 DEG C, after 9000r/min high speed dispersion, mechanical agitation 10min makes colostrum, after regulating pH to 7.2, under pressure is 108MPa condition, carry out homogenizing 7 times, obtain uniform milky solution; Above-mentioned milky solution filters, logical nitrogen-sealed, after 120 DEG C of sterilization treatment 15min, and less than 25 DEG C storages.
Four, the benflumetol lipomul injection prepared of different isoosmotic adjusting agent
Embodiment 7:
Prescription:
1200mg benflumetol is put into 30mL isopropyl alcohol and is fully dissolved into solution; this solution is mixed with long-chain fatty acid ester in 300g injection; the antioxidant vitamin E of 30g injection hydrogenated yolk lecithin, 0.23g is added under nitrogen protection after evaporation removing isopropyl alcohol; in 80 DEG C of mixing, form oil mixture.By 800mL water for injection, 25g glucose, 0.2g Tween 80 in 80 DEG C of mixing, form aqueous mixture.Under nitrogen protection aqueous mixture is mixed with oil mixture, add water to 1000mL, at 80 DEG C, after 10000r/min high speed dispersion, mechanical agitation 5min makes colostrum, after regulating pH to 7.8, under pressure is 110MPa condition, carry out homogenizing 6 times, obtain uniform milky solution; Above-mentioned milky solution filters, logical nitrogen-sealed, after 121 DEG C of sterilization treatment 15min, and less than 25 DEG C storages.
Embodiment 8:
Prescription:
2000mg benflumetol is put into 10mL chloroform and is fully dissolved into solution; this solution is added and 150g injection Oleum Camelliae; add the antioxidant vitamin E of 35g injection Ovum Gallus domesticus Flavus lecithin, 0.29g after evaporation removing chloroform under nitrogen protection, in 70 DEG C of mixing, form oil mixture.By 600mL water for injection, 25g glycerol, 0.6gF68 in 70 DEG C of mixing, form aqueous mixture.Under nitrogen protection aqueous mixture is mixed with oil mixture, add water to 1000mL, at 70 DEG C, after 10000r/min high speed dispersion, mechanical agitation 10min makes colostrum, after regulating pH to 7.4, under pressure is 108MPa condition, carry out homogenizing 7 times, obtain uniform milky solution; Above-mentioned milky solution filters, logical nitrogen-sealed, after 121 DEG C of sterilization treatment 15min, and less than 25 DEG C storages.
The animal experiment study of embodiment 9, benflumetol fat milk ejection preparation
The pharmacodynamic study of 5.1 benflumetol fat milk ejection preparation treatment malaria
5.1.1 animal
Kunming mouse, body weight 22 ± 1g, male and female half and half, Institute of Experimental Animals, Chinese Academy of Medical Sciences provides, the quality certification number: SCXK(capital) 2004-0001; P. berghei worm strain (NK-173, Chinese military medicine academy of science microorganism epidemic diseases provided).
5.1.2 method
Test adopts Peters method.Get Kunming mouse, by body weight random packet, every treated animal 10, male and female half and half, are divided into model control group, benflumetol fat milk administration group (concentration is respectively 90,45,22.5 mg/kg/d), tail drug administration by injection.Model control group does not deal with.The inoculation of mouse peritoneal quantification is respectively organized containing l × 10 during experiment
7individual by the erythrocyte of Mus plasmodium parasitism, inoculum concentration 0.2ml/ only.After inoculation, second day is by group administration, the 4d inhibition test method(s) specified by WHO, successive administration 3 days.
Administration, after 4 days, is got blood from mousetail on the 5th day and is coated with thin smear film sheet, with the dyeing of Giemsa staining, basis of microscopic observation, and counts 1 × 10
3erythrocyte Central Plains borer population, calculates erythrocytic infection rate (%).Examine under a microscope 50 oily mirror visuals field (× 1000, about 2.5 ten thousand erythrocyte), person is decided to be negative blood sheet not observe plasmodium, calculates each dosage group mice negative conversion rate (%) by formula one.
As mice is turned out cloudy, then observe mice resume combustion situation in 30 days, be i.e. be coated with a thin smear film (secondary on every Wendesdays) next day, until 30 days.Observed after 30 days and be still then decided to be healing for negative blood sheet person, and calculate the cure rate (%) of each dosage group mice by formula two.
5.1.3 result
Result is respectively in table 5.1.In mouse blood plasmodium and mice turn out cloudy after the microphotograph of blood see Fig. 1.This shows that benflumetol fat milk has obvious killing action to plasmodium, and can effectively control plasmodial recurrence.
Table 5.1 benflumetol fat milk test of pesticide effectiveness result
5.2 pairs of benflumetol lipomuls of the present invention carry out safety testing
5.2.1 vascular stimulation test:
Test method: every day, to rabbit injection 3.0ml/kg test sample (by the conversion of clinical application amount), after continuous three times, dissects animal blood vessels and makes pathology section examination, the significant stimulation reactions such as inorganization degeneration or necrosis.
5.2.2 hemolytic experiment: undertaken by the method for new drug research safety testing guideline, occur without haemolysis.
5.2.3 systemic anaphylaxis is tested:
Test by the method regulation of the Pharmacopoeia of the People's Republic of China, result of the test: after injecting first the 14th day and 21 days, after benflumetol fat milk excites, in 30min there is not the phenomenon such as perpendicular hair, sneeze, retch, cough, dyspnea, rale, tic, collapse in animal, show that benflumetol fat milk Cavia porcellus systemic anaphylaxis result of the test is for negative, this product is without sensitization.
5.2.4 pyrogen test:
Test method: test with reference to Chinese Pharmacopoeia 2005 editions annex Ⅹ III A pyrogen tests, result shows that benflumetol fat milk is to rabbit blood vessel and the equal nonirritant of muscle, to Cavia porcellus test without anaphylaxis, to rat without passive cutaneous anaphylaxis, without hemolytic and rabbit pyrogen test compound pharmacopeia specified standard.Show that injection benflumetol fat milk meets the requirement of safety indexes.
5.2.5 the stability test of benflumetol fat milk
Get the fat milk of fresh preparation, be placed in centrifuge tube, after the centrifugal 15min of 13000rpm, do not find layering, also have no drug precipitation and separate out.Room temperature cool place place's storage 1 year, all there is not significant change in the physicochemical properties such as Emulsion outward appearance, particle diameter, Zeta potential and content, shows stable emulsion.
Claims (10)
1. a benflumetol fat milk injection, is characterized in that, consists of the following composition:
All the other are water for injection.
2. benflumetol fat milk injection according to claim 1, is characterized in that: described oil for injection is soybean oil, Oleum Camelliae, Oleum Sesami, middle long-chain fatty acid ester, olive oil, Oleum Curcumae, pearl barley oil, Oleum Bulbus Allii, safflower oil, Fructus Zanthoxyli oil, Rhizoma Chuanxiong oil, Herba Artemisiae Annuae oil, Oleum Hippophae, wintergreen oil, Radix Oenotherae erythrosepalae oil, Radix Angelicae Sinensis oil, oil of Rhizoma Zingiberis Recens, Herba Schizonepetae oil, Fructus Forsythiae oil, eucalyptus oil, perilla oil, Oleum Citri Reticulatae, Oleum Viticis Negundo, Oleum Rosae Rugosae, Oleum Ricini, Oleum menthae, oil of Herba Artemisiae Scopariae, fennel oil, pine oil, Oleum Caryophylli, Oleum Anisi Stellati, Oleum thymi vulgaris, Oleum Cinnamomi, Oleum Folium Artemisiae Argyi, Fructus Perillae oil, turmeric oil, Cortex Melaleucae leucadendrae oil, Essential lavender oil, Radix Aucklandiae oil, patchouli oil, Herba Verbenae oil, Common Wormwood oil, Salvia Sclare L.oil, Rhizoma Atractylodis oil, Myrtus communis oil, Fructus Citri Limoniae oil, Fructus Aurantii Immaturus oil, Oleum Ocimi Gratissimi, Folium Perillae oil, art (pine) pomegranate oil, Oleum Cocois, Fructus Amomi oil, olive oil, citronella oil, Oleum Pelargonii Graveolentis, Herba Moslae oil, Oleum Menthae Rotundifoliae, Du Shan oil, Herba Pogostemonis oil, Storax oil, oil of Ribes nigrum L., Fructus Schisandrae oil, Rhizoma Acori Graminei oil, Fructus Cnidii oil, Fructus Phellodendri oil, Oleum lavandula angustifolia, oil of rosemary, oleum bergamottae, sandal oil, Fructus Dauci Sativae oil, Cacumen Cupressi oil, seed oil of Herba Apii graveolentis, Herba Origani oil, citronellal oil, Fructus Coriandri oil, orange blossom oil, Semen Myristicae oil, oil of Bulbus Allii Cepae, Oleum Santali albi, Flos Tagetis Erectae oil, thyme oil, any one or more mixture in Cananga odorata oil.
3. benflumetol fat milk injection according to claim 1, is characterized in that: described emulsifying agent is Ovum Gallus domesticus Flavus lecithin, soybean lecithin, hydrogenated yolk lecithin, hydrogenated soy phosphatidyl choline or synthetic lecithin.
4. benflumetol fat milk injection according to claim 1, is characterized in that: described co-emulsifier be in Tween 80, F68, enuatrol, potassium oleate or oleic acid any one or appoint several.
5. benflumetol fat milk injection according to claim 1, is characterized in that: described solubilizing agent is dehydrated alcohol, chloroform, acetone or isopropyl alcohol.
6. benflumetol fat milk injection according to claim 1, is characterized in that: described isotonic agent is glycerol, glucose or xylitol.
7. benflumetol fat milk injection according to claim 1, is characterized in that: described antioxidant is vitamin E.
8. benflumetol fat milk injection according to claim 1, is characterized in that: be processed into by following composition:
9. the preparation method of any one benflumetol fat milk injection described in claim 1 ~ 7, it is characterized in that, step is as follows:
Step 1: the solubilizing agent that the benflumetol of 0.03 ~ 35wt% puts into 0.5 ~ 10wt% dissolved, then mix with the oil for injection of 10.0 ~ 30.0wt%, evaporates 10 ~ 120min and removes solubilizing agent in 80 DEG C of water-baths; Add the emulsifying agent of 0.6 ~ 30.0wt% and the antioxidant of 0.002 ~ 0.075wt% under nitrogen protection, be heated to 40 ~ 80 DEG C and obtain forming oil mixture;
Step 2: the isotonic agent of 2.25 ~ 7wt%, the co-emulsifier of 0.01 ~ 5wt% and water for injection are mixed at 40 ~ 80 DEG C, forms aqueous mixture;
Step 3: the oil mixture that aqueous mixture step 2 obtained under nitrogen protection and step 1 obtain mixes, then at 40 ~ 80 DEG C, under 5000 ~ 12000r/min condition after high speed dispersion 5 ~ 30min, mechanical agitation 60 ~ 120min again, pH to 6.0 ~ 9.0 are regulated with 0.1mol/L NaOH or HCL, under pressure is 90 ~ 110MPa condition, carry out homogenizing 6 ~ 9 times, obtain uniform milky solution;
Step 4: step 3 gained milky solution is filtered, leads to nitrogen-sealed, through 100 ~ 125 DEG C of sterilization treatment 15 ~ 50min or after 0.22 μm of sterilised membrane filter filters, less than 25 DEG C storages.
10. the application of benflumetol fat milk injection according to claim 1 in the medicine of preparation treatment malaria.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210338450.2A CN102895187B (en) | 2012-09-13 | 2012-09-13 | Preparation of benflumetol fat emulsion for injection and application of benflumetol fat emulsion in treatment of malaria |
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| CN103353487A (en) * | 2013-06-17 | 2013-10-16 | 张家港威胜生物医药有限公司 | High performance liquid chromatography method for determination of lumefantrine content |
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| CN1876187A (en) * | 2006-04-28 | 2006-12-13 | 中国人民解放军军事医学科学院放射与辐射医学研究所 | Double-head radical lipid prodrug |
| CN1915217A (en) * | 2006-08-31 | 2007-02-21 | 广州市医药工业研究所 | Self-emulsifying agent of compound artemether |
| CN101437490A (en) * | 2006-04-20 | 2009-05-20 | 安美基公司 | Stable emulsion formulations |
| CN101940675A (en) * | 2010-09-10 | 2011-01-12 | 重庆市南川区金佛山中药材品种培育研究所 | Chinese medicinal herb for treating facial neuritis |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101437490A (en) * | 2006-04-20 | 2009-05-20 | 安美基公司 | Stable emulsion formulations |
| CN1876187A (en) * | 2006-04-28 | 2006-12-13 | 中国人民解放军军事医学科学院放射与辐射医学研究所 | Double-head radical lipid prodrug |
| CN1915217A (en) * | 2006-08-31 | 2007-02-21 | 广州市医药工业研究所 | Self-emulsifying agent of compound artemether |
| CN101940675A (en) * | 2010-09-10 | 2011-01-12 | 重庆市南川区金佛山中药材品种培育研究所 | Chinese medicinal herb for treating facial neuritis |
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