CN102895187A - 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
- Publication number
- CN102895187A CN102895187A CN2012103384502A CN201210338450A CN102895187A CN 102895187 A CN102895187 A CN 102895187A CN 2012103384502 A CN2012103384502 A CN 2012103384502A CN 201210338450 A CN201210338450 A CN 201210338450A CN 102895187 A CN102895187 A CN 102895187A
- Authority
- CN
- China
- Prior art keywords
- oil
- benflumetol
- oleum
- injection
- fat milk
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Images
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Medicinal Preparation (AREA)
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 the Chinese scholar a kind of effective malaria monomer that separating-purifying goes out from Herba Artemisiae Annuae in early 1970s, it is the sesquiterpene lactone compound that contains the peroxide bridge structure, have fast, efficient, without Drug resistance, hypotoxic characteristics, be called " maximum for the treatment of malaria is wished " by World Health Organization (WHO), can be considered China pharmacy worker to the maximum contribution of human society.Its discovery becomes world's malaria history another important mileage after quinine.But studies show that, take separately for a long time Arteannuin preparation protozoon is developed immunity to drugs, make compound formulation and arteannuin and other malaria medicine united, also can nearly 95% curative effect be arranged to non-concurrent malaria.Therefore, in February, 2004, WHO reforms malaria treatment medication policy, proposes to stop using artemisine folk prescription antimalarial drug, adopt take artemisinin-based drug as basic combination medicine (Artemisinin-based combination therapies is called for short the ACTs therapy) and advocate.At present, this take artemisinin-based drug as the basis combination medicine mainly contain: Artemether-LUMEFANTRINE, artesunate-amodiaquine, artesunate-sulfamethoxine-pyrimethamine, artesunate-mefloquine, amodiaquine and sulfamethoxine-pyrimethamine drug combinations etc., wherein the effect of Artemether-LUMEFANTRINE drug combination is best.This is because Artemether-LUMEFANTRINE drug combination is can potentiation complementary: the artemisinin derivatives Artemether has stronger killing action to the plasmodium schizont, and is evident in efficacy for multiple resistant malaria and anti-Chloroquine-resistant Falciparum Malaria disease.But it exists again action time short, the shortcomings such as relapse rate height.It is totally thorough that benflumetol is killed plasmodium, and effective percentage reaches more than 95%, and relapse rate is lower than 5%, but onset is slow.So will can overcome simultaneously the high and slow shortcoming of benflumetol effect of Artemether relapse rate behind the two recurrence due to taking drug sides.Have the control symptom fast, kill plasmodium thoroughly, the strain of antagonism worm effectively, the advantage such as delay to develop immunity to drugs.And this compound recipe and existing other antimalarial are without cross tolerance, and be 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 compound recipe dosage form of Artemether and benflumetol only has oral formulations, discloses Artemether/benflumetol compound oral tablet, compound oral syrup, compound suppository etc. such as " number of patent application is 90106722.9 Chinese patent "." number of patent application is 200610037383.5 Chinese patent " discloses the self-emulsifier of Artemether/benflumetol compound recipe." number of patent application is 200710057537.1 Chinese patent " discloses the drop pill of Artemether/benflumetol compound recipe." number of patent application is that 200710057538.6 Chinese patent discloses a kind of preparation method for the treatment of the benflumetol dripping pill of malaria ".These all are peroral dosage forms, when clinical use, can not be used for the emergency treatment of malaria, although they are at the oral administration biaavailability that has improved in varying degrees benflumetol simultaneously, but because the fatty dependency of benflumetol (be the impact that the oral absorption of benflumetol is subjected to food, eat food rich in fat during patient's drug administration, just can have higher drug absorption rate and higher blood drug level to kill the malaria worm) so that benflumetol need to increase the clinical therapeutic efficacy that taking dose and number of times ensure medicine when oral.So benflumetol dosage when clinical use even reaches 2880mg up to 1840mg, taking of so long-term high dose can be accelerated drug-fast generation, thereby greatly shortens the service life of benflumetol, reduces result of use.In addition from patient's angle, high dose, frequently take medicine and increase undoubtedly financial burden, in fact, the high main barrier that has become malaria patients' treatment at present of expense.In order to overcome defects, be necessary to develop the novel form of benflumetol.
Fat milk injection is a kind of new fat-soluble medicine carrier.It is take soybean oil as main component, is emulsifying agent with refined lecithin, and 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.Simultaneously, it can also improve malnourished patient's lymphocyte activity, for the patient provides nutrition, is highly suitable for the emergency treatment of subtertian malaria and general malaria.
In sum, in order to protect the clinical service life 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, satisfy the demand that the pernicious treatment malaria of clinical treatment is used for injection, the invention provides a kind of benflumetol injection is the benflumetol lipomul.
Owing to be injection, so its bioavailability is 100%.It need not to add any cosolvent when being used for injection, therefore reduced the incidence rate of toxic and side effects, and it can also improve patient's lymphocyte activity for malaria patients provide health required nutrition, helps the patient to 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 the Cananga odorata oil.
Wherein, described emulsifying agent is any in Ovum Gallus domesticus Flavus lecithin, soybean lecithin, hydrogenated yolk lecithin, hydrogenated soy phosphatidyl choline, the synthetic lecithin;
Wherein, described co-emulsifier be in Tween 80, F68, enuatrol, potassium oleate, the oleic acid any or appoint several;
Wherein, described solubilizing agent is any of dehydrated alcohol, chloroform, acetone or isopropyl alcohol;
Wherein, described isotonic agent is any of glycerol, glucose or xylitol.
Wherein, described antioxidant is vitamin E.
The present invention also provides the preparation method of benflumetol fat milk injection, may further comprise the steps:
Step 1: the solubilizing agent of the benflumetol of 0.03～35wt% being put into 0～10wt% is dissolved, and then mixes with the oil for injection of 10.0～30.0wt%, evaporates 10～120min and remove solubilizing agent in 80 ℃ of water-baths; Under nitrogen protection, add the emulsifying agent of 0.6～30.0wt% and the antioxidant of 0.002～0.075wt%, be heated to 40～80 ℃ and obtain forming oil mixture;
Step 2: the isotonic agent of 2.25～7wt%, co-emulsifier and the water for injection of 0 ~ 5wt% are mixed under 40 ~ 80 ℃, form aqueous mixture;
Step 3: the aqueous mixture that under nitrogen protection step 2 is obtained mixes with the oil mixture that step 1 obtains, then at 40～80 ℃, under 5000～12000r/min condition behind high speed dispersion 5～30min, mechanical agitation 60～120min again, regulate pH to 6.0～9.0 with 0.1mol/L NaOH or HCL, be to carry out homogenizing under 90～110MPa condition 6～9 times at pressure, obtain uniform milky solution;
Step 4: step 3 gained milky solution is filtered, leads to nitrogen-sealed, through 100～125 ℃ of sterilization treatment 15 ~ 50min or behind the aseptic membrane filtration of 0.22 μ m, storage below 25 ℃.
The present invention also provides the application of benflumetol fat milk injection in the treatment malaria.This pharmaceutical dosage form can be intramuscular injection or intravenous injection.Detect (seeing 5.1 for details) according to antimalarial active in the body, respectively organize during experiment quantitatively to inoculate in the mouse peritoneal and contain l * 10
7Individual by the erythrocyte of Mus plasmodium parasitism, inoculum concentration 0.2ml/ only.Second day is pressed the 4d inhibition test method(s) of WHO regulation, successive administration 3 days by the group administration after inoculation.Benflumetol fat milk administration group (concentration is respectively 90,45,22.5 mg/kg/d), endnote is penetrated administration.The result shows that the negative conversion rate of each benflumetol fat milk injection administration group mice is 100%, illustrates that the benflumetol fat milk has good antimalarial active, can be used for malaria treatment.
The benflumetol fat milk injection of the inventive method preparation brings up to 100% with the bioavailability of benflumetol.And, can utilize fat milk to suppress the characteristic of growth of malaria parasites, nutrition supply, the antimalarial effect of enhancing benflumetol for malaria patients provide health required nutrition, is improved patient's lymphocyte activity simultaneously, helps the patient to resist malaria and rehabilitation.The benflumetol fat milk injection of the inventive method preparation can be directly used in injection, no longer needs the hydrotropy carrier, thereby has reduced the toxic and side effects to human body, can increase the stability of medicine simultaneously.
Description of drawings
Fig. 1: contain plasmodium (Figure 1A) in the mouse blood and turn out cloudy after do not contain the microphotograph of plasmodium (Figure 1B)
The specific embodiment
The present invention verifies the amount ranges of various adjuvants in the pharmaceutical formulation of injection benflumetol fat milk.Below in conjunction with embodiment the present invention is elaborated, but be not limited only to following example.
One, the benflumetol lipomul injection of different oil phase preparations
Embodiment 1:
Prescription:
The 30mg benflumetol is put into 2mL acetone fully be dissolved into solution; this solution is mixed with 10g injection soybean oil; the antioxidant vitamin E that adds 1.2g injection Ovum Gallus domesticus Flavus lecithin, 0.02g behind the acetone under nitrogen protection is removed in evaporation, in 60 ℃ of mixing, forms oil mixture.50mL water for injection, 0.4g enuatrol and 2.5g glycerol in 60 ℃ of mixing, are formed aqueous mixture.Under nitrogen protection, aqueous mixture is mixed with oil mixture, and add water to 100mL, under 60 ℃, mechanical agitation 20min makes colostrum after the 6500r/min high speed dispersion, after regulating pH to 7.0, be homogenizing 8 times under the 105MPa condition at pressure, obtain uniform milky solution; Above-mentioned milky solution filters, logical nitrogen-sealed, behind 115 ℃ of sterilization treatment 15min, and storage below 25 ℃.
Embodiment 2:
Prescription:
The 500mg benflumetol is put into the 4mL chloroform fully be dissolved into solution; this solution is mixed with 10g injection Oleum Camelliae; the antioxidant vitamin E that adds 1.2g injection lecithin, 0.02g behind the chloroform under nitrogen protection is removed in evaporation, in 70 ℃ of mixing, forms oil mixture.70mL water for injection, 2.5g xylitol, 0.2g F68 in 70 ℃ of mixing, are formed aqueous mixture.Under nitrogen protection, aqueous mixture is mixed with oil mixture, add water to 100mL, under 70 ℃, mechanical agitation 20min makes colostrum after the 7000r/min high speed dispersion, after regulating pH to 7.5, be to carry out homogenizing under the 90MPa condition 9 times at pressure, obtain uniform milky solution; Above-mentioned milky solution filters, logical nitrogen-sealed, behind 120 ℃ of sterilization treatment 25min, and storage below 25 ℃.
Two, the benflumetol lipomul injection of different emulsifiers preparation
Embodiment 3:
Prescription:
The 300mg benflumetol is put into 6mL acetone fully be dissolved into solution; this solution is mixed with 20g injection Oleum Sesami; the antioxidant vitamin E that adds 2.4g injection Ovum Gallus domesticus Flavus lecithin, 0.02g behind the acetone under nitrogen protection is removed in evaporation, in 70 ℃ of mixing, forms oil mixture.150mL water for injection, 5g glycerol, 0.02g oleic acid in 70 ℃ of mixing, are formed aqueous mixture.Under nitrogen protection, aqueous mixture is mixed with oil mixture, add water to 200mL, under 70 ℃, mechanical agitation 20min makes colostrum after the 7500r/min high speed dispersion, after regulating pH to 8.0, be to carry out homogenizing under the 95MPa condition 6 times at pressure, obtain uniform milky solution; Above-mentioned milky solution filters, logical nitrogen-sealed, behind 125 ℃ of sterilization treatment 10min, and storage below 25 ℃.
Embodiment 4:
Prescription:
The 120mg benflumetol is put into the 3mL isopropyl alcohol fully be dissolved into solution; this solution is mixed with long-chain fatty acid ester in the 30g injection; the antioxidant vitamin E that adds 1.2g injection hydrogenated yolk lecithin, 0.02g behind the isopropyl alcohol under nitrogen protection is removed in evaporation; in 60 ℃ of mixing, form oil mixture.50mL water for injection, 2.5g glycerol, 0.4g F68 in 70 ℃ of mixing, are formed aqueous mixture.Under nitrogen protection, aqueous mixture is mixed with oil mixture, add water to 100mL, under 70 ℃, mechanical agitation 15min makes colostrum after the 8000r/min high speed dispersion, after regulating pH to 8.0, be to carry out homogenizing under the 100MPa condition 8 times at pressure, obtain uniform milky solution; Above-mentioned milky solution filters, logical nitrogen-sealed, behind 100 ℃ of sterilization treatment 30min, and storage below 25 ℃.
Three, the benflumetol lipomul injection of different co-emulsifier preparations
Embodiment 5:
Prescription:
The 400mg benflumetol is put into the 4mL chloroform fully be dissolved into solution; this solution is mixed with 200g injection soybean oil; the antioxidant vitamin E that adds 12g injection lecithin, 0.15g behind the chloroform under nitrogen protection is removed in evaporation, in 60 ℃ of mixing, forms oil mixture.900mL water for injection, 25g glycerol, 0.4g F68 in 60 ℃ of mixing, are formed aqueous mixture.Under nitrogen protection, aqueous mixture is mixed with oil mixture, add water to 1000mL, under 60 ℃, mechanical agitation 15min makes colostrum after the 8900r/min high speed dispersion, after regulating pH to 7.8, be to carry out homogenizing under the 110MPa condition 6 times at pressure, obtain uniform milky solution; Above-mentioned milky solution filters, logical nitrogen-sealed, behind 125 ℃ of sterilization treatment 10min, and storage below 25 ℃.
Embodiment 6:
Prescription:
The 700mg benflumetol is put into the 8mL chloroform fully be dissolved into solution; this solution is mixed with 300g injection Oleum Camelliae; the antioxidant vitamin E that adds 24g injection Ovum Gallus domesticus Flavus lecithin, 0.21g behind the chloroform under nitrogen protection is removed in evaporation, in 70 ℃ of mixing, forms oil mixture.900mL water for injection, 25g glycerol, 0.04g oleic acid in 70 ℃ of mixing, are formed aqueous mixture.Under nitrogen protection, aqueous mixture is mixed with oil mixture, add water to 1000mL, under 70 ℃, mechanical agitation 10min makes colostrum after the 9000r/min high speed dispersion, after regulating pH to 7.2, be to carry out homogenizing under the 108MPa condition 7 times at pressure, obtain uniform milky solution; Above-mentioned milky solution filters, logical nitrogen-sealed, behind 120 ℃ of sterilization treatment 15min, and storage below 25 ℃.
Four, the benflumetol lipomul injection of different isoosmotic adjusting agent preparations
Embodiment 7:
Prescription:
The 1200mg benflumetol is put into the 30mL isopropyl alcohol fully be dissolved into solution; this solution is mixed with long-chain fatty acid ester in the 300g injection; the antioxidant vitamin E that adds 30g injection hydrogenated yolk lecithin, 0.23g behind the isopropyl alcohol under nitrogen protection is removed in evaporation; in 80 ℃ of mixing, form oil mixture.800mL water for injection, 25g glucose, 0.2g Tween 80 in 80 ℃ of mixing, are formed aqueous mixture.Under nitrogen protection, aqueous mixture is mixed with oil mixture, add water to 1000mL, under 80 ℃, mechanical agitation 5min makes colostrum after the 10000r/min high speed dispersion, after regulating pH to 7.8, be to carry out homogenizing under the 110MPa condition 6 times at pressure, obtain uniform milky solution; Above-mentioned milky solution filters, logical nitrogen-sealed, behind 121 ℃ of sterilization treatment 15min, and storage below 25 ℃.
Embodiment 8:
Prescription:
The 2000mg benflumetol is put into the 10mL chloroform fully be dissolved into solution; this solution is added and 150g injection Oleum Camelliae; the antioxidant vitamin E that adds 35g injection Ovum Gallus domesticus Flavus lecithin, 0.29g behind the chloroform under nitrogen protection is removed in evaporation, in 70 ℃ of mixing, forms oil mixture.600mL water for injection, 25g glycerol, 0.6gF68 in 70 ℃ of mixing, are formed aqueous mixture.Under nitrogen protection, aqueous mixture is mixed with oil mixture, add water to 1000mL, under 70 ℃, mechanical agitation 10min makes colostrum after the 10000r/min high speed dispersion, after regulating pH to 7.4, be to carry out homogenizing under the 108MPa condition 7 times at pressure, obtain uniform milky solution; Above-mentioned milky solution filters, logical nitrogen-sealed, behind 121 ℃ of sterilization treatment 15min, and storage below 25 ℃.
The animal experiment study of embodiment 9, benflumetol fat milk ejection preparation
5.1 the pharmacodynamic study of 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: the SCXK(capital) 2004-0001; Bai Shi plasmodium worm strain (NK-173, Chinese military medicine academy of science microorganism epidemic diseases provides).
5.1.2 method
The Peters method is adopted in test.Get Kunming mouse, by body weight random packet, 10 of every treated animals, 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), and endnote is penetrated administration.Model control group does not deal with.Respectively organize during experiment quantitatively to inoculate in the mouse peritoneal and contain l * 10
7Individual by the erythrocyte of Mus plasmodium parasitism, inoculum concentration 0.2ml/ only.Second day is pressed the 4d inhibition test method(s) of WHO regulation, successive administration 3 days by the group administration after inoculation.
After the administration 4 days, got blood from mousetail on the 5th day to be coated with the thin smear film sheet, with the dyeing of Giemsa staining, microscopically is observed, 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), the person is decided to be negative blood sheet not observe the plasmodium, by formula one calculates each dosage group mice negative conversion rate (%).
Turn out cloudy such as mice, then observe mice resume combustion situation in 30 days, be i.e. be coated with a thin smear film (inferior on every Wendesdays) next day, until 30 days.Observed afterwards still by 30 days that negative blood sheet person then is decided to be healing, and two cure rates (%) that calculate each dosage group mice by formula.
5.1.3 result
The result sees Table respectively 5.1.The turn out cloudy microphotograph of rear blood of plasmodium and mice is seen Fig. 1 in the mouse blood.This shows that the 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 benflumetol lipomul of the present invention is carried out safety testing
5.2.1 vascular stimulation test:
Test method: every day is 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 the pathology sections observation, inorganization degeneration or the significant stimulation reaction such as downright bad.
5.2.2 the hemolytic experiment: the method by new drug research safety testing guideline is carried out, and occurs without haemolysis.
5.2.3 systemic anaphylaxis experiment:
Method regulation by the Pharmacopoeia of the People's Republic of China is tested, result of the test: rear the 14th day and 21 days of first injection, the phenomenons such as perpendicular hair, sneeze, retch, cough, dyspnea, rale, tic, collapse do not appear in animal in the 30min after the benflumetol fat milk excites, show that benflumetol fat milk Cavia porcellus systemic anaphylaxis result of the test is negative, this product is without sensitization.
5.2.4 pyrogen test:
Test method: test with reference to 2005 editions appendix X of Chinese Pharmacopoeia III A pyrogen test, the result shows that the benflumetol fat milk is to rabbit blood vessel and the equal nonirritant of muscle, Cavia porcellus is tested without anaphylaxis, to rat without passive cutaneous anaphylaxis, without hemolytic and the compound pharmacopeia specified standard of rabbit pyrogen test.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, place centrifuge tube, behind the centrifugal 15min of 13000rpm, do not find layering, also have no drug precipitation and separate out.The shady and cool place of room temperature stores 1 year, and significant change does not all occur for the physicochemical property such as Emulsion outward appearance, particle diameter, Zeta potential and content, shows that Emulsion is stable.
Claims (10)
1. a benflumetol fat milk injection is characterized in that, is processed into by following composition:
All the other are water for injection.
2. benflumetol fat milk injection according to claim 1, it 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 the Cananga odorata oil.
3. benflumetol fat milk injection according to claim 1, it 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 the oleic acid any or appoint several.
5. benflumetol fat milk injection according to claim 1, it is characterized in that: described solubilizing agent is dehydrated alcohol, chloroform, acetone or isopropyl alcohol.
6. benflumetol fat milk injection according to claim 1, it is characterized in that: described isotonic agent is glycerol, glucose or xylitol.
7. benflumetol fat milk injection according to claim 1, it 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 the described arbitrary benflumetol fat milk injection of claim 1～7 is characterized in that step is as follows:
Step 1: the solubilizing agent of the benflumetol of 0.03～35wt% being put into 0～10wt% is dissolved, and then mixes with the oil for injection of 10.0～30.0wt%, evaporates 10～120min and remove solubilizing agent in 80 ℃ of water-baths; Under nitrogen protection, add the emulsifying agent of 0.6～30.0wt% and the antioxidant of 0.002～0.075wt%, be heated to 40～80 ℃ and obtain forming oil mixture;
Step 2: the isotonic agent of 2.25～7wt%, co-emulsifier and the water for injection of 0 ~ 5wt% are mixed under 40 ~ 80 ℃, form aqueous mixture;
Step 3: the aqueous mixture that under nitrogen protection step 2 is obtained mixes with the oil mixture that step 1 obtains, then at 40～80 ℃, under 5000～12000r/min condition behind high speed dispersion 5～30min, mechanical agitation 60～120min again, regulate pH to 6.0～9.0 with 0.1mol/L NaOH or HCL, be to carry out homogenizing under 90～110MPa condition 6～9 times at pressure, obtain uniform milky solution;
Step 4: step 3 gained milky solution is filtered, leads to nitrogen-sealed, through 100～125 ℃ of sterilization treatment 15 ~ 50min or behind the aseptic membrane filtration of 0.22 μ m, storage below 25 ℃.
10. the application of benflumetol fat milk injection claimed in 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 |
Applications Claiming Priority (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 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102895187A true CN102895187A (en) | 2013-01-30 |
| CN102895187B CN102895187B (en) | 2015-05-06 |
Family
ID=47567877
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210338450.2A Expired - Fee Related 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 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102895187B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| WO2014180011A1 (en) * | 2013-05-09 | 2014-11-13 | 西安力邦制药有限公司 | Preparation of artemether/benflumetol compound fat emulsion for injection, and application of same in malaria treatment |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
-
2012
- 2012-09-13 CN CN201210338450.2A patent/CN102895187B/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014180011A1 (en) * | 2013-05-09 | 2014-11-13 | 西安力邦制药有限公司 | Preparation of artemether/benflumetol compound fat emulsion for injection, and application of same in malaria treatment |
| 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 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102895187B (en) | 2015-05-06 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN100569294C (en) | A kind of used for intravenous injection high stable long-circulation fat fat breast carrying medicine | |
| CN1709398B (en) | Filtering-degerming Chinese medicine or animal-plant volatile oil or fat emulsion and preparing method | |
| WO2006039231A2 (en) | Topical formulations for the treatment of depression with s adenosyl methionine | |
| CN104146957A (en) | Submicroemulsion antifungal drug spray preparation | |
| CN101954070A (en) | Preparation method of composition of nano SOD and vegetable drugs and health-care food or extracts thereof | |
| CN101658494A (en) | Huperzine A solid lipid nano particle and preparation method thereof | |
| CN101601695B (en) | Self-microemulsion nanometer composition of ganodenic acid extract and preparation method thereof | |
| CN101982109A (en) | Method for preparing cinnamon oil microemulsion | |
| CN102895186B (en) | The preparation of artesunate for Injection fat milk and medicinal application thereof | |
| CN106619588A (en) | Self-microemulsion nutrient composition containing coenzyme Q10 and preparation method and application | |
| CN100506225C (en) | Pharmaceutical use, medicine composition and preparation process of angelica oil components | |
| CN102283895A (en) | Preparation technology and production method of integrated novel Lingguizhugan decoction dosage form | |
| CN102895187B (en) | Preparation of benflumetol fat emulsion for injection and application of benflumetol fat emulsion in treatment of malaria | |
| US20070042009A1 (en) | Topical composition for delivery of salicylates | |
| CN102258467B (en) | Formula and preparation of intravenous injection sustained-release fat emulsion of arteannuin and derivative thereof | |
| CN1985851A (en) | Lipoid microsphere injection containing toad cake extract and its preparing method | |
| CN1771968A (en) | Ursolic acid fat emulsion injection and its prepn | |
| CN103251584A (en) | Preparation of artemether/benflumetol compound fat emulsion for injection and application of artemether/benflumetol compound fat emulsion in malaria treatment | |
| CN1899440A (en) | Yujin medicinal emulsion preparation | |
| CN100579523C (en) | Dihydroartemisinin emulsion for injection, freeze-dried emulsion and preparation method thereof | |
| JP4690334B2 (en) | Oral microemulsion composition comprising biphenyldimethyldicarboxylate and silybin | |
| CN1810240A (en) | Prepn process and use of total andrographolide emulsion | |
| CN102949415B (en) | Propolis fat emulsion preparation and preparation method thereof | |
| CN1290495C (en) | Lipid microspherical asarol prepn and its prepn process | |
| CN102008434B (en) | Compound docetaxel ester microsphere injection and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20190920 Address after: 350001 V-01, 4th Floor, 28 Hot Spring Park Road, Hot Spring Street, Gulou District, Fuzhou City, Fujian Province (Business Trusteeship) Patentee after: Fuzhou Xinruip Pharmaceutical Technology Co.,Ltd. Address before: 710075 No. two, No. 18, hi tech Road, Shaanxi, Xi'an Patentee before: XI'AN LIBANG PHARMACEUTICAL Co.,Ltd. |
|
| TR01 | Transfer of patent right | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20150506 Termination date: 20210913 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |