CN1596882A - Vitamin K1 emulsion and its freeze-dried emulsion and preparation method - Google Patents
Vitamin K1 emulsion and its freeze-dried emulsion and preparation method Download PDFInfo
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- CN1596882A CN1596882A CN 200410021537 CN200410021537A CN1596882A CN 1596882 A CN1596882 A CN 1596882A CN 200410021537 CN200410021537 CN 200410021537 CN 200410021537 A CN200410021537 A CN 200410021537A CN 1596882 A CN1596882 A CN 1596882A
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Abstract
A VK1 emulsion and its freeze-dried emulsion containing freeze protecting agent are prepared from VK1, oil phase, emulsifier, stabilizer, penetration pressure regulator and pH regulator.
Description
Technical field:
The present invention relates to medical technical field, exactly it is a kind of vitamin K
1Emulsion and freeze-dried emulsion thereof and preparation method.
Background technology:
Vitamin K
1Its chemical name is: 2-methyl-3-(3,7,11,15-tetramethyl-2-hexadecene base)-1,4-naphthalenedione.This product is a vitamin drug, is liver composition-factor II, VII, IX, the necessary material of X.Vitamin K deficiency can cause these thrombin dyssynthesises or unusual, clinical visible bleeding tendency and prolonged prothrombin.Vitamin K and blood coagulation are closely related, during shortage, can cause the dyssynthesis of liver to multiple thrombin, cause body cruor time extending and bleeding tendency, and in time vitimin supplement K can make coagulation function recover.Vitamin K
1Also have direct hepatoprotective and antiinflammation,, bilirubin level is descended, and reach and fall the enzyme effect jaundice and the ALT rising person due to the hepatitis.Clinical vitamin K commonly used is treated the digestive tract hemorrhage that liver cirrhosis causes.Fatsoluble vitamin K commonly used
1, intramuscular injection or intravenous drip, each 10 milligrams, every day 2 times.Indication: what be used for that vitamin K deficiency causes is hemorrhage, as hemorrhage due to obstructive jaundice, leak, the chronic diarrhea etc., vitamin K deficiency in the body due to the Hypoprothrombinemia due to Coumarins, the sodium salicylate etc., hemorrhage of newborn and prolonged application broad ectrum antibiotic.
Vitamin K
1Injection records in " Chinese Pharmacopoeia 2000 version two ones ", and used solubilizing agent is a tween 80, because tween 80 is a polyoxyethylene 20 sorbitan monooleate, this material has haemolysis, and easily oxidation takes place, and oxidation product can cause allergy.In addition, vitamin K
1Dissolubility is very poor in the water, and made injection is placed at low temperature muddiness is easily taken place, and is difficult under the room temperature recover, and needs heating, could dissolve again.Because the polyoxyethylene in the tween 80 combines with anhydrous sorbitol in the ehter bond mode, vivo degradation is slow, and blood coagulation resisting function is also slow, is unfavorable for emergence therapeutic.
In addition, neonate is easily suffered from tardy property vitamin K deficiency, and easily mistaken diagnosis clinically, morbidity is anxious, the state of an illness is heavy, prognosis mala when being associated with intracranial hemorrhage, and case fatality rate is up to 18%～50%, and majority is left over permanent nervous system sequela.The intravenous injection vitamin K is emphasized in the treatment of primary disease
1Lay equal stress on blood transfusion.And advocate that young infant is adhered to the principle that medication prevents in 3 months.Main preventive measure has at present: (1) normal term newborn, premature infant, low birth weight infant, all answer conventional intramuscular injection vitamin K1 0.5～1mg after the birth, logotype 3 days.Oral medication is invalid.(2) respectively inject vitamin K when giving birth to 1～2 week of back, full moon and 3 months the time
11 time, can effectively prevent the intracranial hemorrhage due to the primary disease.(3) the conventional vitimin supplement K of neonate later stage wet nurse, and the nutraceutical such as green vegetable, fruit, animal livers, Semen Glycines, egg yolk of taking food in right amount can improve vitamin K content in the breast milk.(4) young infant of long-term diarrhea or trouble liver and gall diseases, intramuscular injection vitamin K weekly
15mg.Because the safety issue of tween 80 in the existing injection, a kind of quality of necessary exploitation is higher, the better K of safety
1Injection.
Oil concentration in the existing Emulsion injection is 10%, 20% or 30%, finds that by a large amount of tests oil concentration is high more, and the performance of drug effect is slow more, as be the vitamin K that solvent prepares with 10%, 20% or 30%
1Injection, under Isodose, the docking clotting time of mice obviously is longer than the clotting time of low concentration fat injection, is unfavorable for the clinical treatment application.
Summary of the invention:
The purpose of this invention is to provide a kind of vitamin K
1Emulsion and freeze-dried emulsion thereof, and provide a kind of technology simple preparation method, it can improve medicine stability, safety, accelerates the performance of curative effect of medication, is beneficial to emergence therapeutic.
It is to contain the vitamin K of effective dosage
1As medicine, and contain pharmaceutic adjuvants such as oil phase, emulsifying agent, stabilizing agent, osmotic pressure regulator, pH regulator agent, contain freeze drying protectant in the freeze-dried emulsion, its Chinese medicine: oil=1: 0～1: 50.
Its prescription and technology are as follows:
Injectable emulsion: contain in every 1-10ml medicinal liquid:
Vitamin K
12～100mg
Oil for injection 10～500mg
Emulsifying agent is an amount of
Stabilizing agent is an amount of
Glycerol is an amount of
The pH regulator agent is an amount of
The best applications dosage of oil for injection is 50-300mg; Can be the vegetable oil of any kind of, as: one or more mixture in Oleum Glycines, Oleum Camelliae, olive oil, the Flos Carthami wet goods.Granularity is 50nm-1000nm.
Emulsifying agent: one or more mixture in phospholipid (soybean lecithin, Ovum Gallus domesticus Flavus lecithin), poloxamer, HS15 (Polyethylene Glycol 12-hydroxy stearic acid ester, polyethylene glycol 660 hydroxystearate as a nonionic solubilizerfor injection solutions), the vitamin E polyethylene glycol succinic acid ester (tocopherol polyethyleneglycol succinate TPGS) etc., consumption is 1-200mg.
Stabilizing agent: one or more mixture in nitrogen, anhydrous sodium sulphuric acid (hydrogen) sodium, sodium thiosulfate, sodium pyrosulfite, vitamin C (Vc), dibenzylatiooluene, alpha-tocopherol, α-tocopheryl acetate, the hydroquinone etc., consumption is 1-100mg.
The pH regulator agent: one or more mixture in hydrochloric acid, sodium hydroxide, sodium acetate, acetic acid, phosphate, the citric acid etc., adjusting pH is 3-9.
Antiseptic: benzyl alcohol, consumption are 0-20mg.
The injection freeze-dried emulsion:
Contain in every 1-10ml medicinal liquid:
Vitamin K
12～50mg
Oil for injection 0-50mg
Emulsifying agent is an amount of
Stabilizing agent is an amount of
The pH regulator agent is an amount of
Antiseptic is an amount of
Freeze drying protectant is an amount of
The best applications dosage of oil for injection is 0-50mg; Can be the vegetable oil of any kind of, as: one or more mixture in Oleum Glycines, Oleum Camelliae, olive oil, the Flos Carthami wet goods.Granularity is 10nm-1000nm.
Emulsifying agent, stabilizing agent, pH regulator agent etc. require identical with Emulsion.
Antiseptic: parabens, consumption are 0-10mg.
Freeze drying protectant: one or more mixture in glucose, lactose, mannitol, sorbitol, xylitol, sucrose, trehalose, dextran, the polyvinylpyrrolidone (PVP) etc., the content of freeze drying protectant is 4%-40% (W/V).
Prepared freeze-dried emulsion is measured on demand and is added water, is recovered to Emulsion, intramuscular injection or intravenously administrable after the hydration vibration.Experimental result shows that the Emulsion of the present invention's preparation has improved vitamin K greatly
1Stability, see " embodiment 11 ".
Preparation process is as follows:
1, prepare oil phase (medicine phase) in preparing tank: in preparing tank, oil for injection is heated to 20-90 ℃ when medicine (simple non-refuelling), adds emulsifying agent, strong agitation is to dissolving in the time of 20～50 ℃; Be cooled to 20～40 ℃ again, in stirring, add medicine.
2, in preparing tank, prepare water: water and glycerol are stirred 5min down at 20～90 ℃, make it complete miscibility.
3, in the time of 20～50 ℃, water is added in the oil phase, strong agitation 10～30min forms colostrum.
4, colostrum is crossed G
3The funnel sucking filtration is regulated pH value to 3～9.
5, cross the homogenizing instrument, the first step is regulated homogenize pressure to 520～600kg/cm
2, second step re-adjustment to 100～140kg/cm
2(or the microjet instrument, the first step is regulated homogenize pressure to 4000-8000psi, and the second step re-adjustment is to 10000-16000psi), form Emulsion.Cross microporous filter membrane, packing (add freeze drying protectant, carry out lyophilization, promptly get freeze-dried emulsion), sterilization promptly gets injectable emulsion.
Vitamin K
1Assay analyze with HPLC:
The chromatographic condition of HPLC is: the chromatographic column octadecylsilane chemically bonded silica
The mobile phase dehydrated alcohol
Detect wavelength 254nm
Particle size analyzer: use PSS.NICOMPTM 380 in this experiment as the instrument of measuring particle diameter.
Advantage of the present invention is:
Improved the plain K of dimension significantly
1Stability and curative effect, for extensive patients provides safer, stable, effective preparation.And technology is simple, is easy to realize.
Be illustrated with embodiment below, but be not limited to listed embodiment:
Embodiment 1: prescription is formed: vitamin K
10.2g, alpha-tocopherol 0.01g, injection soybean oil 1g, soybean lecithin 1.2g, glycerol 2.2g, 0.01g anhydrous sodium sodium bisulfate 0.01g, become 100ml altogether.
1, in dosing apparatus, with vitamin K
10.2g, the 0.01g alpha-tocopherol is dissolved in mix homogeneously in the 1g injection soybean oil;
2,, and add 0.01g anhydrous sodium sodium bisulfate with the soybean lecithin of 1.2g, the glycerol of 2.2g (anhydrous) and proper amount of water for injection mix homogeneously;
3, with 2) under stirring condition, add 1) in, get colostrum after in the time of 20 ℃, stirring, cross G
3The funnel sucking filtration, (first step is regulated homogenize pressure to 520kg/cm to gained liquid by even matter instrument
2, the second step re-adjustment is to 100/cm
2) (or the microjet instrument, the first step is regulated homogenize pressure to 4000psi, and the second step re-adjustment is to 10000psi), form Emulsion.With solution homogenize repeatedly, obtain uniform solution; Regulating pH with sodium hydroxide and hydrochloric acid is 3.0, makes medicinal liquid 100ml altogether.Cross the 0.45um microporous filter membrane, after the degerming of 0.22um microporous filter membrane, 100 grades are aseptic subpackaged down, every 1ml, and inflated with nitrogen seals, and promptly gets vitamin K
1Injectable emulsion (adding benzyl alcohol 9mg in case of necessity).Granularity is: 50～500nm.Particle mean size 236nm
Embodiment 2: prescription is formed: vitamin K
11g, injection olive oil 10g, Ovum Gallus domesticus Flavus lecithin 1.2g, glycerol 2.2g, anhydrous sodium sulfite 0.01g become 100ml altogether.
Method is with " embodiment 1 "
1, in the dosing apparatus, with vitamin K
11.0g be dissolved in mix homogeneously in the 10g injection olive oil;
2,, and add the 0.01g anhydrous sodium sulfite with the Ovum Gallus domesticus Flavus lecithin of 1.2g, the glycerol of 2.2g (anhydrous) and proper amount of water for injection mix homogeneously;
3, with 2) under stirring condition, add 1) in, in the time of 40 ℃, stir the back by even matter instrument, with solution homogenize repeatedly (microjet instrument, the first step are regulated homogenize pressure to 8000psi, and the second step re-adjustment is to 16000psi), obtain uniform solution; Regulating pH with sodium hydroxide and acetic acid is 6.0.Homogenizer is handled, and makes medicinal liquid 100ml altogether.Packing, every 1ml, inflated with nitrogen seals, and flowing steam sterilization 30 minutes promptly gets vitamin K
1Injectable emulsion.
Granularity is: 80～1000nm.
Embodiment 3: prescription is formed: vitamin K
1The HS15 10g of 1g, alpha-tocopherol 0.1g, injection olive oil 50g, 10g, glycerol 22g, anhydrous sodium sulfite 0.5g, 0.1g vitamin C 0.1g becomes 1000ml altogether.Method is with " embodiment 1 "
1, in the control equipment, with vitamin K
11.0g, the 0.1g alpha-tocopherol is dissolved in mix homogeneously in the 50g injection olive oil;
2, with the glycerol (anhydrous) and proper amount of water for injection mix homogeneously of HS15 (Polyethylene Glycol 12-hydroxy stearic acid ester, polyethylene glycol 660hydroxystearate), the 22g of 10g; Add 0.5g anhydrous sodium sulfite, 0.1g vitamin C;
3, with 2) under stirring condition, add 1) in, in the time of 90 ℃, stir the back by even matter instrument, with solution homogenize repeatedly (microjet instrument, the first step are regulated homogenize pressure to 7000psi, and the second step re-adjustment is to 14000psi), obtain uniform solution; Regulating pH with sodium hydroxide and phosphoric acid is 6.0.Homogenizer is handled, and makes medicinal liquid 1000ml altogether.Packing, logical nitrogen, every 10ml (10mg); Or 2ml (2mg), flowing steam sterilization 30 minutes promptly gets vitamin K
1Injectable emulsion.Granularity is: 50～800nm.
Embodiment 4: prescription is formed: vitamin K
11g, alpha-tocopherol 0.1g, injection soybean oil 10g, Ovum Gallus domesticus Flavus lecithin 10g, glycerol 2.2g, 1.0g vitamin E polyethylene glycol succinic acid ester 1.0g become 500ml altogether.Method is with " embodiment 1 "
1, in the dosing apparatus, with vitamin K
11.0g, the 0.1g alpha-tocopherol is dissolved in mix homogeneously in the 10g injection soybean oil;
2, the glycerol (anhydrous) of the Ovum Gallus domesticus Flavus lecithin of 10.0g, 1.0g vitamin E polyethylene glycol succinic acid ester (tocopherol polyethyleneglycol succinate TPGS), 2.2g and proper amount of water for injection mix homogeneously;
3, under stirring condition, add in 12, in the time of 50 ℃, stir the back,, obtain uniform solution solution homogenize repeatedly (microjet instrument, the first step are regulated homogenize pressure to 7000psi, and the second step re-adjustment is to 16000psi) by even matter instrument; With sodium hydroxide and Fructus Citri Limoniae acid for adjusting pH is 7.0.Homogenizer is handled, and makes medicinal liquid 500ml altogether.Packing, logical nitrogen, every 5ml (10mg/5ml); Or 1ml (2mg/1ml), flowing steam sterilization 30 minutes promptly gets vitamin K
1Injectable emulsion.Granularity is: 50～800nm.
Embodiment 5: prescription is formed: vitamin K
11g, alpha-tocopherol 0.1g, 10g injection safflower oil 10g, soybean lecithin 2.0g, 1.0g poloxamer F68, glycerol 2.2g become 100ml altogether.
Method is with " embodiment 1 "
1, in the dosing apparatus, with vitamin K
11.0g, the 0.1g alpha-tocopherol is dissolved in mix homogeneously in the 10g injection safflower oil;
2, the glycerol (anhydrous) of the soybean lecithin of 2.0g, 1.0g poloxamer F68,2.2g and proper amount of water for injection mix homogeneously;
3, under stirring condition, add in 12, in the time of 50 ℃, stir the back,, obtain uniform solution solution homogenize repeatedly (microjet instrument, the first step are regulated homogenize pressure to 6000psi, and the second step re-adjustment is to 14000psi) by even matter instrument; Regulating pH with sodium hydroxide and hydrochloric acid is 9.0.Homogenizer is handled, and makes medicinal liquid 100ml altogether.Packing, logical nitrogen, every 2ml (20mg/ props up), flowing steam sterilization 30 minutes promptly gets vitamin K
1Injectable emulsion.Granularity is: 80～900nm.
Embodiment 6:
Prescription is formed: vitamin K
10.2g, the soybean lecithin of 2g, 0.1g alpha-tocopherol, 10g sucrose, total amount 100ml.
1. in the dosing apparatus, with vitamin K
11.0g, 0.1g alpha-tocopherol mix homogeneously;
2, the soybean lecithin of 2g is scattered in proper amount of water for injection, mix homogeneously;
3, with 2) under stirring condition, add 1) in, get colostrum after in the time of 20 ℃, stirring, cross G
3The funnel sucking filtration, gained liquid forms Emulsion by even matter instrument (microjet instrument, the first step are regulated homogenize pressure to 4000psi, and the second step re-adjustment is to 12000psi).With solution homogenize repeatedly, obtain uniform solution; Regulating pH with sodium hydroxide and hydrochloric acid is 3.0～4.0, adds 10g sucrose, makes medicinal liquid 100ml altogether.Cross the 0.3um microporous filter membrane, packing, every 1ml (10mg) removes moisture through lyophilization, gets vitamin K
1Freeze-dried emulsion.
4, will make freeze-dried emulsion and measure on demand and add water, be recovered to Emulsion after the hydration vibration.Granularity 10nm～400nm.
Embodiment 7:
Prescription is formed: vitamin K
11.0g, the Ovum Gallus domesticus Flavus lecithin of 10g, 0.1g anhydrous sodium sodium bisulfate, 10g mannitol, 2g glucose, total amount 200ml.
1, in the dosing apparatus, adds vitamin K
11.0g;
2, the Ovum Gallus domesticus Flavus lecithin of 10g is scattered in proper amount of water for injection, mix homogeneously;
3, under stirring condition, add in 12, get colostrum after in the time of 40 ℃, stirring, cross G
3The funnel sucking filtration, gained liquid forms Emulsion by even matter instrument (microjet instrument, the first step are regulated homogenize pressure to 6000psi, and the second step re-adjustment is to 16000psi).With solution homogenize repeatedly, obtain uniform solution; With sodium hydroxide and Fructus Citri Limoniae acid for adjusting pH is 5.0～7.0, adds 8g mannitol, 4g glucose, makes medicinal liquid 200ml altogether.Cross the 0.22um microporous filter membrane, packing, every 2ml (10mg) removes moisture through lyophilization, and inflated with nitrogen gets vitamin K
1Freeze-dried emulsion.
4, will make freeze-dried emulsion and measure on demand and add water, be recovered to Emulsion after the hydration vibration.Granularity 10nm～300nm.
Embodiment 8:
Prescription is formed: vitamin K
11.0g, 10g HS15,1g injection soybean oil, 0.5g vitamin C, 50g mannitol, total amount 1000ml.
1, in the control equipment, adds vitamin K
11.0g, 1g injection soybean oil, the dissolving mixing;
2,10g HS15 is scattered in the water for injection of 500ml, adds the 0.5g vitamin C, mix homogeneously;
3, under stirring condition, add in 12, get colostrum after in the time of 40 ℃, stirring, cross G
3The funnel sucking filtration, gained liquid forms Emulsion by even matter instrument (microjet instrument, the first step are regulated homogenize pressure to 5000psi, and the second step re-adjustment is to 15000psi).With solution homogenize repeatedly, obtain uniform solution; Regulating pH with sodium hydroxide and phosphoric acid is 6.0～8.0, adds 50g mannitol, and the dissolving back adds water for injection to 1000ml.Cross the 0.22um microporous filter membrane, packing, every 2ml (2mg) removes moisture through lyophilization, and inflated with nitrogen gets vitamin K
1Freeze-dried emulsion.
4, will make freeze-dried emulsion and measure on demand and add water, be recovered to Emulsion after the hydration vibration.Granularity 10nm～400nm.
Embodiment 9:
Prescription is formed: vitamin K
11.0g, 5g injection soybean oil, 2g Ovum Gallus domesticus Flavus lecithin, 4g vitamin E polyethylene glycol succinic acid ester (tocopherol polyethyleneglycol succinate TPGS), nitrogen, sorbitol 3g, trehalose 5g, ethyl hydroxybenzoate 0.01g, total amount 100ml.
1, in the configuration device, adds vitamin K
11.0g, 5g injection soybean oil, the dissolving mixing;
2,2g Ovum Gallus domesticus Flavus lecithin, 4g vitamin E polyethylene glycol succinic acid ester (tocopherol polyethyleneglycol succinate TPGS) are scattered in the water for injection of 50ml, mix homogeneously;
3, under stirring condition, add in 12, get colostrum after in the time of 60 ℃, stirring, cross G
3The funnel sucking filtration, gained liquid forms Emulsion by even matter instrument (microjet instrument, the first step are regulated homogenize pressure to 5000psi, and the second step re-adjustment is to 15000psi).With solution homogenize repeatedly, obtain uniform solution; With sodium hydroxide and hydrochloric acid acid for adjusting pH is 7.0～9.0, adds sorbitol 3g, trehalose 5g, ethyl hydroxybenzoate 0.01g, and the dissolving back adds water for injection to 100ml.Cross the 0.22um microporous filter membrane, packing, every 2ml removes moisture through lyophilization, and inflated with nitrogen gets vitamin K
1Freeze-dried emulsion.
4, will make freeze-dried emulsion and measure on demand and add water, be recovered to Emulsion after the hydration vibration.Granularity 30nm～1000nm.
Embodiment 10:
Prescription is formed: the 1g vitamin K
1, 4g soybean lecithin, 0.1g anhydrous sodium sulfite, 6g mannitol, 6g glucose, total amount 200ml.
1, in the dosing apparatus, adds the 1g vitamin K
1
2, the soybean lecithin of 4g is scattered in proper amount of water for injection, mix homogeneously;
3, with 2) under stirring condition, add 1) in, get colostrum after in the time of 40 ℃, stirring, cross G
3The funnel sucking filtration, gained liquid forms Emulsion by even matter instrument (microjet instrument, the first step are regulated homogenize pressure to 6000psi, and the second step re-adjustment is to 16000psi).With solution homogenize repeatedly, obtain uniform solution; With sodium hydroxide and Fructus Citri Limoniae acid for adjusting pH is 7.0～9.0, adds 6g mannitol, 6g glucose, makes medicinal liquid 200ml altogether.Cross the 0.22um microporous filter membrane, packing, every 2ml (10mg) removes moisture through lyophilization, and inflated with nitrogen seals, and gets the vitamin E freeze-dried emulsion.Particle mean size is 212nm.
4, will make freeze-dried emulsion and measure on demand and add water, be recovered to Emulsion after the hydration vibration.Granularity 10nm～398nm.Particle mean size is 206nm.
Embodiment 11: different preparation illumination experimental results see Table 1.
Table 1: medicine stability test result
Commercially available injection EXAMPLE Example EXAMPLE Example embodiment
Liquid 1
0 o'clock 100% 100% 100% 100% 100% 100%
Illumination 10 days 63.1% 93.2% 92.8% 93.3% 97.6% 98.8%
Hence one can see that, with vitamin K
1After making Emulsion and freeze-dried emulsion, medicine stability improves greatly.
Embodiment 12: to the mice influence in docking bleeding time.Adopt mice docking method.Get 90 of mices, body weight 18-22g, male and female half and half are divided into 3 groups at random by sex, body weight, every group 10, behind the intravenous administration 1 hour, cut mouse tail 3mm place with profit cross-section, timing, inhale the section drop of blood gently once every 30 seconds with filter paper, till blood stops (depletion of blood when filter paper is inhaled) naturally, calculate the bleeding time, compare between organizing.The results are shown in Table 2.
Table 2, to the influence in mice docking bleeding time
Group dosage animal (only) bleeding time (min, X ± SD)
(mg/Kg)
Normal saline (NS) 10 7.71 ± 1.02
Commercially available injection 3 10 6.06 ± 0.88
*
Commercially available injection 6 10 5.38 ± 0.76
*
Vitamin K
1Fat 3 10 6.52 ± 0.91
*
Emulsion
Vitamin K
1Fat 6 10 5.67 ± 0.87
*
Emulsion
Embodiment 13 10 4.16 ± 0.53
*
Embodiment 16 10 3.07 ± 0.41
*
Embodiment 63 10 4.03 ± 0.44
*
Embodiment 66 10 3.16 ± 0.41
*
Compare with the NS matched group:
*P＜0.05,
*P＜0.01; Compare with existing preparation, this product clotting time obviously shortens, and has significant difference, with vitamin K
1Lipomul (soybean oil is 10%) compares, and the clotting time of embodiment 1,6 also obviously shortens, and it is former because in lipomul, because the soybean oil consumption is 10%, and vitamin K
1Discharging needs the regular hour, causes the slow result of onset.
Embodiment 13: the haemolysis of treatment Hua Faling (another name Warfarin Warfarin)
Hua Faling (another name Warfarin Warfarin) can with vitamin K
1The phase antagonism can only be used vitamin K by the haemolysis that Hua Faling causes
1, can not use vitamin K
3This research is the different vitamin Ks of comparison
1Preparation method spirit to China (Warfarin Warfarin) destroys the therapeutical effect of the blood coagulation factor.Method: 40 of rabbit, 5 every group, per os 0.1mg/Kg behind the administration Hua Faling, gives different preparations by 2mg/Kg, measures clotting time, the results are shown in Table 3.
The different vitamin Ks of table 3.
1Preparation method spirit to China destroys the therapeutical effect result of the blood coagulation factor
Group dosage (mg/Kg) animal (only) bleeding time
(h，X±SD)
NS 2 5 -
Commercially available injection 25 11.6 ± 3.6
*
Vitamin K
1Fat milk 25 7.3 ± 3.3
*
Agent
Embodiment 125 2.7 ± 1.5
*
Embodiment 425 4.1 ± 1.5
*
Embodiment 625 2.8 ± 1.4
*
Embodiment 725 2.9 ± 0.9
*
Embodiment 825 2.6 ± 0.7
*
Compare with commercially available injection:
*P＜0.05,
*P＜0.01.Hence one can see that, and with respect to existing injection and lipomul, this preparation has significant advantage, is more conducive to clinical treatment.
Claims (8)
1, a kind of vitamin K
1Emulsion and freeze-dried emulsion thereof is characterized in that: the vitamin K that contains effective dosage
1As medicine, and contain pharmaceutic adjuvants such as oil phase, emulsifying agent, stabilizing agent, osmotic pressure regulator, pH regulator agent, contain freeze drying protectant in the freeze-dried emulsion, its Chinese medicine: oil=1: 0～1: 50.
2, vitamin K according to claim 1
1Emulsion and freeze-dried emulsion thereof is characterized in that: can contain antiseptic in the pharmaceutic adjuvant.
3, vitamin K according to claim 1
1Emulsion is characterized in that:
Its prescription is:
Contain in every 1-10ml medicinal liquid:
Vitamin K
12～100mg
Oil for injection 10～500mg
Emulsifying agent is an amount of
Stabilizing agent is an amount of
Glycerol is an amount of
Antiseptic is an amount of
The pH regulator agent is an amount of
4, vitamin K according to claim 1
1Freeze-dried emulsion is characterized in that:
Its prescription is:
Contain in every 1-10ml medicinal liquid:
Vitamin K
12～50mg
Oil for injection 0-50mg
Emulsifying agent is an amount of
Stabilizing agent is an amount of
The pH regulator agent is an amount of
Antiseptic is an amount of
Freeze drying protectant is an amount of
5, vitamin K according to claim 2
1Emulsion is characterized in that:
The application dose of oil for injection is 50-300mg; Can be one or more mixture in the vegetable oil of Oleum Glycines, Oleum Camelliae, olive oil, Flos Carthami wet goods any kind of, granularity be 50nm-1000nm;
Emulsifying agent is one or more mixture in phospholipid, poloxamer, HS15 (Polyethylene Glycol 12-hydroxy stearic acid ester, polyethyleneglycol 660 hydroxystearate), the vitamin E polyethylene glycol succinic acid ester (TPGS) etc., and consumption is 10-200mg.
Stabilizing agent is one or more mixture in nitrogen, anhydrous sodium sulphuric acid (hydrogen) sodium, Vc, dibenzylatiooluene, alpha-tocopherol, α-tocopheryl acetate, the hydroquinone etc., and consumption is 1mg-100mg;
Antiseptic is a benzyl alcohol, and consumption is 0-20mg;
The pH regulator agent is one or more mixture in hydrochloric acid, sodium hydroxide, sodium acetate, acetic acid, phosphate, the citric acid etc., and adjusting pH is 3-9.
6, vitamin K according to claim 3
1Freeze-dried emulsion is characterized in that:
The application dose of oil for injection can be 0-50mg; Can be one or more mixture in the plant wet goods of Oleum Glycines, Oleum Camelliae, olive oil, Flos Carthami wet goods any kind of, granularity be 10nm-1000nm.
Emulsifying agent, stabilizing agent, pH regulator agent etc. require identical with Emulsion.
Antiseptic is a parabens, and consumption is 0-10mg;
Freeze drying protectant is one or more mixture in glucose, lactose, mannitol, sorbitol, xylitol, sucrose, trehalose, dextran, the polyvinylpyrrolidone (PVP) etc., and the content of freeze drying protectant is 4%-40% (W/V);
Prepared freeze-dried emulsion is measured on demand and is added water, is recovered to Emulsion, intramuscular injection or intravenously administrable after the hydration vibration.
7, vitamin K according to claim 5
1Freeze-dried emulsion is characterized in that: freeze drying protectant is the combination of glucose and mannitol, and both proportionings are: 1: 0.01～0.01: 1.
8, a kind of vitamin K as claimed in claim 2
1The preparation method of Emulsion is characterized in that:
1) prepare oil phase (medicine phase) in the preparing tank:
In preparing tank, oil for injection is heated to 20-90 ℃, non-refuelling during simple medicine adds emulsifying agent then, and strong agitation is to dissolving in the time of 20～50 ℃; Be cooled to 20～40 ℃ again, in stirring, add medicine;
2) in preparing tank, prepare water:
Water and glycerol are stirred 5min down at 20～90 ℃, make it complete miscibility;
3) in the time of 20～50 ℃, water is added in the oil phase, strong agitation 10～30min forms colostrum;
4) colostrum is crossed G3 funnel sucking filtration, regulated pH value to 3～9;
5) cross the homogenizing instrument, the first step is regulated homogenize pressure to 520～600kg/cm
2, second step re-adjustment to 100～140kg/cm
2Or cross the microjet instrument, and the first step is regulated homogenize pressure to 4000-8000psi, and the second step re-adjustment forms Emulsion to 10000-16000psi, crosses microporous filter membrane, packing; Add freeze drying protectant, carry out lyophilization, promptly get freeze-dried emulsion, sterilization promptly gets injectable emulsion.
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| CN 200410021537 CN1596882A (en) | 2004-07-22 | 2004-07-22 | Vitamin K1 emulsion and its freeze-dried emulsion and preparation method |
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| Application Number | Priority Date | Filing Date | Title |
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| CN 200410021537 CN1596882A (en) | 2004-07-22 | 2004-07-22 | Vitamin K1 emulsion and its freeze-dried emulsion and preparation method |
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| CN1596882A true CN1596882A (en) | 2005-03-23 |
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| CN101327202B (en) * | 2006-06-23 | 2011-05-11 | 杭州平和安康医药科技有限公司 | Vitamin K1 lyophilized powder for injection and preparation method |
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