CN100486587C - Clarithromycin liposome microsphere injection and its preparation method - Google Patents
Clarithromycin liposome microsphere injection and its preparation method Download PDFInfo
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Abstract
A lipide microball type injection of clarithromycin with high stability and low toxin is prepared from the oil for injection, clarithromycin, surfactant, glycerin, oil-phase solubilizer, metallic chelating agent, and the water for injection. Its preparing process is also disclosed.
Description
Invention field
The present invention relates to medical technical field, exactly the present invention relates to lipide microsphere injection of a kind of clarithromycin and preparation method thereof.
Background of invention
(clarithromycin, CAM) chemistry 6-O-erythromycin by name is a Macrolide third generation derivant, shown in the following surface chemistry structural formula to clarithromycin.Because at C
6The position has increased methoxy group (OCH
3), therefore to compare clarithromycin more stable to acid with erythromycin.
Clarithromycin is widely used in the treatment such as the helicobacter pylori infections of infectious disease and noninfectious disease clinically, the infection of respiratory tract and skin soft tissue bacterial infection, biofilm disease, tuberculosis, mycobacterium, the infection of Elastolyticenzyme of pseudomonas aeruginosa biofilm, sexually transmitted disease (STD), antitumor, treatment morbid state thyroid syndrome, arteriosclerosis, reduction serum thrombin, bronchial asthma.Total effective rate with the upper and lower respiratory tract infection of clarithromycin treatment acute and chronic is 88.5-96.0%, and effective percentage scorching to male urethra and cervicitis is respectively 91.7% and 96.8%.To children's's otitis media effective percentage is 96%, and prostatitis is 80.0%, and the skin soft-tissue infection effective percentage is 87.5%.Also can treat legionnaires disease and leprosy etc. clinically.It is reported that the clarithromycin dry syrup is the unique children's's oral antibiotic that can control main Gram-positive, feminine gender and atypia pathogenic bacterium.To unique curative effect of mycoplasma, chlamydia infection, be that other antibiotic are too far behind to catch up.
The clarithromycin good absorbing, long half time, penetration power is strong in tissue and the cell, blood drug level is balanced.Oral administration biaavailability is about 50%, and plasma protein binding rate is about 70%, and excretion is 35% in the urine.Main metabolites is the 14-OH clarithromycin with antibacterial activity.Be distributed in very soon after clarithromycin is taken in each tissue and the body fluid, concentration is higher than serum.
U.S. Abbott released clarithromycin in 1991, and dosage form has tablet, dry syrup, intravenous injection, later stage that oral suspensions and slow releasing tablet are arranged successively.And present domestic have only tablet, capsule and granule.
The problem of using the existing dosage form of clarithromycin is to have untoward reaction, mainly contain halitosis (3%), stomachache, diarrhoea, feel sick, GI irritation reaction (2%-3%) such as vomiting, headache (2%), accidental erythra, skin are itched etc. after the infant medications that anaphylaxis infects 20 examples, dizzy, weak, nauseating in the infant, diarrhoea, a granulocyte example that descends, alkali phosphatase 2 examples that raise, lactic acid dehydrogenase and creatine kinase raise simultaneously, an example raises separately.Intravenous injection clarithromycin lactobionic acid injection has serious zest to blood vessel wall, easily causes chemical phlebitis; And because medicine itself has than strong and stimulating, also can cause vasospasm, blood reduces.These problems have a strong impact on promoting the use of of this medicine.
Chinese patent application number: 200410012384.5 have disclosed a kind of " clarithromycin injectable emulsion and preparation method thereof ".But the clarithromycin of being set forth in this patent and the preparation method of Emulsion thereof have serious defective.The dissolubility of clarithromycin in water and in the oil is all bad, is 200ug/ml (ph=6.8) in the water, and in the oil＜2mg/ml, by testing the medicine that 30% oil phase can only dissolve about 100mg, this dosage does not reach the medicinal specification of 500mg/100ml far away.If the oil suspension of clarithromycin is added to the water as oil phase, become breast back clarithromycin from oil, to separate out, settle.If the pH value of Emulsion is adjusted to 4.0, in the process of sterilization, clarithromycin also can be separated out, and settles, and Emulsion also can breakdown of emulsion.Can't also can not be prepared into the Emulsion or the clarithromycin lipide microsphere injection of clarithromycin as from the foregoing by this patent at all.
Therefore In view of the foregoing, bring into play clinical efficacy better for making clarithromycin, the research and development novel form, advantage efficient, low toxicity with novel form is given full play to the clarithromycin antibacterial activity and is reduced toxic and side effects, and this undoubtedly will be significant to further promotion and the application of popularization clarithromycin in clinical.
Summary of the invention
Purpose of the present invention is exactly to overcome the defective that existing dosage forms of clarithromycin exists, and a kind of clarithromycin lipide microsphere injection (oil in water emulsion) of injection for intravenous is provided, and its preparation method also is provided simultaneously.This clarithromycin lipide microsphere injection provided by the invention, wherein clarithromycin can be dissolved in wherein the oil phase well, thus, and this lipide microsphere injection good stability, evident in efficacy, reduced zest and the toxic and side effects of clarithromycin to blood vessel.
One object of the present invention just provides a kind of lipide microsphere injection of clarithromycin.
Another object of the present invention provides a kind of method for preparing the lipide microsphere injection of described clarithromycin.
The objective of the invention is to realize by the following technical solutions:
A kind of lipide microsphere injection of clarithromycin, in the quality of said preparation, it comprises:
Oil for injection 2%～50%,
Clarithromycin 0.1%～2%,
Surfactant 0.2%～10%,
Glycerol 0.2%～10%,
Oil phase solubilizing agent 0.1%～5%,
Metal-chelator 0%～2%,
Water for injection 40～90%
The used oil phase solubilizing agent of the present invention is C
5-C
18Satisfied fatty acid, preferred valeric acid, caproic acid, enanthic acid, sad, n-nonanoic acid, capric acid, oleic acid or its be mixture arbitrarily.Most preferably be caproic acid, oleic acid, and the mixture of arbitrary proportion.By the quality of described preparation, the consumption of oil phase solubilizing agent is 0.1-5%, preferred 0.2-2%.
The term " oil for injection " that the present invention uses is meant the acceptable oily matter of a big class physiology, comprises mineral oil, vegetable oil, animal oil, quintessence oil or artificial oil, or its mixture.By the quality of described preparation, the consumption of oil for injection is 2%-50%, and is preferred 5%-30%, more preferably 10%-20%.Mineral oil can be derived from oil, comprises fat or cerul hydrocarbon, and aromatic hydrocarbon or blended fat and aromatic radical hydrocarbon, mineral oil also comprise the oil such as the refined paraffin wax wet goods of petroleum derivation.Vegetable oil is mainly derived from seed or nut, comprises drying oil such as Semen Lini oil and Oleum Verniciae fordii; Semi-drying oil such as safflower oil, soybean oil and Semen Maydis oil; Non-drying oil such as Oleum Ricini, Oleum Gossypii semen, Petiolus Trachycarpi oil and Oleum Cocois.Animal oil is usually from as sebum, Adeps Sus domestica and stearic fat.Aqueous animal oil comprises fish oil, oleic acid, spermaceti wet goods.Aqueous fatty oil such as single, double, triglyceride, or its mixture.
According to the present invention, preferred, oil for injection is selected from safflower oil, soybean oil, and Semen Maydis oil, Oleum Ricini, the C6-C12 fatty acid triglycercide, and composition thereof.Most preferably be selected from soybean oil, the C7-C9 fatty acid triglycercide, and composition thereof.
Used surfactant can be medicinal any surfactant, is generally phospholipid, cholesterol, tween (Tween), pluronic F68 (poloxamer), enuatrol, oleic acid, cholic acid, deoxycholic acid and composition thereof.Described phospholipid is selected from lecithin, fabaceous lecithin, and composition thereof.Described tween is selected from polysorbas20, polysorbate40, and polysorbate60, Tween 80, polysorbate85, and composition thereof.Preferably, used surfactant is selected from lecithin, fabaceous lecithin, and cholesterol, enuatrol, oleic acid, Tween 80, pluronic F68, and composition thereof.By the quality of described preparation, the consumption of surfactant is 0.2-10%, preferred 0.5%-5%.
Described metal-chelator is disodium edetate (disodium EDTA), sodium calcium edetate (calcium disodium salt of EDTA), and composition thereof.By the quality of described preparation, the consumption of metal-chelator is 0%-2%, preferred 0.1-1%.
By the quality of described preparation, the consumption of clarithromycin is 0.1-2%, preferred 0.1-1%; The consumption of glycerol is 0.2%～10%, preferred 0.5%-5%.
The lipide microsphere injection of clarithromycin of the present invention can also contain an amount of medicinal acid or alkali, and described acid is preferably hydrochloric acid, and described alkali is preferably sodium hydroxide.
The present invention also provides the preparation method of described clarithromycin lipide microsphere injection, and it may further comprise the steps:
1) clarithromycin with recipe quantity is dissolved in the oil phase solubilizing agent, mixes with the oil for injection of recipe quantity again, forms oil phase, and magnetic agitation also is heated to 30-100 ℃;
2) surfactant, metal-chelator and glycerol are dispersed in the part water for injection, magnetic agitation makes it to be uniformly dispersed, and is heated to 30-100 ℃, as water;
3) under magnetic agitation, oil phase is joined aqueous phase, add the back and continue to stir, get colostrum;
4) with the colostrum homogenate under the 15000-30000rpm condition for preparing, up to obtaining milky emulsion;
5) in this emulsion, add remaining water for injection, under 700-900bar high pressure, adopt high pressure homogenizer to carry out homogenizing, form the microgranule of particle diameter, promptly get clarithromycin emulsion of the present invention at 150-260nm.
The clarithromycin that comprises in the injection of the present invention is an insoluble drug, in water and the dissolubility in the oil phase all bad, dissolubility is 0.4mg/ml during pH7.0 in water, the dissolubility in long-chain and midchain oil is less than 2mg/ml.In order to increase the dissolubility of clarithromycin in oil phase, the present invention has adopted the oil phase solubilizing agent, this oil phase solubilizing agent has the electric charge opposite with clarithromycin, can combine with clarithromycin, offset electrical that clarithromycin has, shield the polar group of clarithromycin, increased the dissolubility of clarithromycin in oil phase thus, reached the clinical application specification.The present invention also by making the clarithromycin drug powder become ultramicro powder under highly compressed bump, increases its specific surface area, thereby has increased the dissolubility of clarithromycin in oil phase.At first, under high-speed stirred, can obtain a kind of oil droplet of ultra micro and medicine fine particle and be dispersed in coarse dispersion system in the water simultaneously.Second step, this dispersion is carried out a high pressure homogenize process, high speed airflow bump forms a kind of supersonic speed and stirs, and drug particles is diminished rapidly and is penetrated in the oil or in the oil-water interfacial film with tiny microcrystalline form.
Clarithromycin lipid microsphere injection of the present invention, because clarithromycin is wrapped in oil phase or the oil-water interfacial film, this " isolation " played the effect that increases stability, avoided with body fluid until contacting, thereby reduced issuable part of medicine self and blood vessel irritation.In addition, clarithromycin is by slowly discharge the untoward reaction that can avoid medicine to cause owing to the initial stage excessive concentration in the oil phase when injection in vivo.Clarithromycin lipid microsphere injection of the present invention is the small particle of particle diameter about 200nm, it can be engulfed by the phagocyte of the reticular tissue system of body and be trapped in the reticular tissue system (as liver, lung etc.), have targeting, to drug effect is provided, to reduce toxic and side effects particularly important.
The present invention has improved the drug loading of clarithromycin in Emulsion, has guaranteed curative effect, has reduced its toxicity and zest, and the clarithromycin lipid microsphere injection that the present invention simultaneously makes has good stable, for clinical application provide newly by way of.
Description of drawings
Fig. 1 is drug level and time chart.
The specific embodiment
The following example is in order further to describe the present invention for example, rather than limits the present invention by any way.
Embodiment 1: a kind of clarithromycin lipide microsphere injection, and it comprises following component:
Injection Oleum Ricini 10g
Clarithromycin 0.5g
Lecithin 3g
Glycerol 2.5g
Caproic acid 0.6g
Water for injection 100ml
Its preparation method is as follows:
1) the 0.5g clarithromycin is dissolved in 0.6g in the acid, mixes with 10g injection Oleum Ricini, form oil phase, magnetic agitation also is heated to 60 ℃;
2) 3g lecithin and 2.5g glycerol are dispersed in the 80ml water for injection, magnetic agitation makes it to be uniformly dispersed, and is heated to 60 ℃, as water;
3) under magnetic agitation, oil phase is joined aqueous phase, add the back and continue to stir 10 minutes, get colostrum;
4) with colostrum homogenate 10 minutes under the 30000rpm condition of preparation, repeat 3 times, obtain milky emulsion;
5) in this emulsion, add remaining 20ml water for injection, under the 900bar high pressure, adopt high pressure homogenizer to carry out homogenizing, form the microgranule of particle diameter about 200nm, promptly get clarithromycin emulsion of the present invention, fill, inflated with nitrogen seals and makes finished product.
Embodiment 2: a kind of clarithromycin lipide microsphere injection, and it comprises following component:
Injection Semen Maydis oil 33g
Clarithromycin 0.7g
Fabaceous lecithin 0.3g
Glycerol 8.8g
Oleic acid 3g
Water for injection 64ml
Its preparation method is as follows:
1) the 0.7g clarithromycin is dissolved in the 3g oleic acid, mixes with 33g injection Semen Maydis oil, form oil phase, magnetic agitation also is heated to 50 ℃;
2) 0.3g fabaceous lecithin and 8.8g glycerol are dispersed in the 50ml water for injection, magnetic agitation makes it to be uniformly dispersed, and is heated to 50 ℃, as water;
3) under magnetic agitation, oil phase is joined aqueous phase, add the back and continue to stir 15 minutes, get colostrum;
4) with colostrum homogenate 15 minutes under the 20000rpm condition of preparation, repeat 3 times, obtain milky emulsion;
5) in this emulsion, add remaining 14ml water for injection, under the 900bar high pressure, adopt high pressure homogenizer to carry out homogenizing, form the microgranule of particle diameter about 200nm, promptly get clarithromycin emulsion of the present invention, fill, inflated with nitrogen seals and makes finished product.
Embodiment 3: a kind of clarithromycin lipide microsphere injection, and it comprises following component:
C7-C9 fatty acid triglycercide 10g
Clarithromycin 1g
Tween 80 3g
Glycerol 5g
N-nonanoic acid 2g
Water for injection 79ml
Its preparation method is as follows:
1) the 1g clarithromycin is dissolved in the 2g n-nonanoic acid, mixes with 10g C7-C9 fatty acid triglycercide, form oil phase, magnetic agitation also is heated to 80 ℃;
2) 3g Tween 80 and 5g glycerol are dispersed in the 60ml water for injection, magnetic agitation makes it to be uniformly dispersed, and is heated to 80 ℃, as water;
3) under magnetic agitation, oil phase is joined aqueous phase, add the back and continue to stir 12 minutes, get colostrum;
4) with colostrum homogenate 15 minutes under the 20000rpm condition of preparation, repeat 3 times, obtain milky emulsion;
5) in this emulsion, add remaining 19ml water for injection, under the 800bar high pressure, adopt high pressure homogenizer to carry out homogenizing, form the microgranule of particle diameter about 200nm, promptly get clarithromycin emulsion of the present invention, fill, inflated with nitrogen seals and makes finished product.
Embodiment 4: a kind of clarithromycin lipide microsphere injection, and it comprises following component:
C7-C9 fatty acid triglycercide 6g
Clarithromycin 1g
Cholesterol 2g
Glycerol 1g
Capric acid 1g
EDTA 1g
Water for injection 88ml
Its preparation method is as follows:
1) the 1g clarithromycin is dissolved in the 1g capric acid, mixes with 6g C7-C9 fatty acid triglycercide, form oil phase, magnetic agitation also is heated to 70 ℃;
2) 2g cholesterol, 1gEDTA and 1g glycerol are dispersed in the 70ml water for injection, magnetic agitation makes it to be uniformly dispersed, and is heated to 70 ℃, as water;
3) under magnetic agitation, oil phase is joined aqueous phase, add the back and continue to stir 15 minutes, get colostrum;
4) with colostrum homogenate 15 minutes under the 15000rpm condition of preparation, repeat 3 times, obtain milky emulsion;
5) in this emulsion, add remaining 18ml water for injection, under the 800bar high pressure, adopt high pressure homogenizer to carry out homogenizing, form the microgranule of particle diameter about 200nm, promptly get clarithromycin emulsion of the present invention, fill, inflated with nitrogen seals and makes finished product.
Pharmacodynamics embodiment
Below by pharmacodynamic experiment the effect of clarithromycin lipide microsphere injection of the present invention is described:
One. clarithromycin lipide microsphere injection irritation test
(1) blood vessel irritation experiment
Select 6 of New Zealand white rabbit for use, 3 white rabbits are in auris dextra auricular vein injection Kelamycin injection Qs, and left ear is injected 5% aseptic glucose injection of same dose in contrast; 3 white rabbits are in auris dextra auricular vein injection clarithromycin lipide microsphere injection Qz of the present invention (embodiment 1) in addition, and left ear is injected 5% aseptic glucose injection of same dose in contrast.Once a day, continuous three days, the last administration was after 24 hours, put to death white rabbit, the response situation of perusal injection site, and dissect rabbit ear blood vessel and surrounding tissue is done paraffin section, dyeing, light microscopy checking.
The result shows: two kinds of dosage form blood vessel irritation experiments of Kelamycin injection and clarithromycin lipid microsphere of the present invention perusal is the result show: the blood vessel irritation of Qz is weaker than Qs; Microscopy report shows: the Qs group has to a certain degree blood vessel irritation to New Zealand white rabbit ear blood vessel, and the Qz group is not seen obvious irritation to New Zealand white rabbit ear blood vessel.
(2) muscle irritation experiment
Select 4 of New Zealand white rabbit for use, 2 of every kind of dosage forms, respectively at right lateral thigh musculus quadriceps injection Qs and Qz injection 1ml, aseptic 5% glucose injection of left side quadriceps femoris injection equivalent is injected after 48 hours in contrast, puts to death white rabbit, dissect and take out quadriceps femoris, vertically cut, observe the response situation of injection site muscular tissue, determine the order of reaction.
0 grade: no change.
1 grade: mild hyperaemia, its scope is below 0.5cm * 1.0cm.
2 grades: moderate hyperemia, its scope is more than 0.5cm * 1.0cm.
3 grades: severe hyperemia, with myodegeneration.
4 grades: necrosis occurs, the brown degeneration is arranged.
5 grades: the popularity necrosis occurs.
Calculate 4 quadriceps femoris order of reaction summations then, test again if the difference of the peak of the quadriceps femoris order of reaction and minimum, then should be got 2 healthy rabbits in addition greater than 2.After obtaining the result, if 4 quadriceps femoris order of reaction summations, think then that the local irritation experiment of test sample is up to specification less than 10.
The result shows: the muscle irritation of Qz is weaker than Qs.
Two. the hemolytic experiment
Get blood 20ml from the common carotid artery of New Zealand white rabbit, place in the flask, stir gently, after several minutes, remove and defibrinate, take out blood, add equivalent 5% glucose injection with Glass rod, centrifugal, remove supernatant; Sedimentary erythrocyte adds 5% glucose injection again and cleans, and is centrifugal.Transparent until supernatant so repeatedly, be made into 2% suspension with 5% glucose injection by erythrocytic capacity.
Get 7 of clean tube, number respectively, add each liquid in the following table successively, the 6th pipe does not add test liquid as the blank pipe, the 7th effective distilled water replaces 5% glucose injection, whether shake up, place 37 ℃ of water-baths, observing respectively at 0.5 hour, 1 hour, 2 hours, 3 hours has haemolysis to take place.
The result shows: Qs, Qz do not see that haemolysis takes place, and the hemolytic experiment of two kinds of dosage forms is all qualified.
Three. the anaphylaxis experiment
Get 8 of healthy guinea pigs, two kinds of dosage forms of Qs, Qz each 4, every corresponding test liquid 0.5ml of guinea pig intraperitoneal injection, the next day once, totally three times.The the 14th, the 21 day corresponding reagent liquid 1ml (the dosage conversion is the same) that supplies of lateral vein injection outside the hind paw of every Cavia porcellus after injection first attacks.Each intravenously administrable was observed 2 hours, as two or more person who occurs grabbing in nose, perpendicular hair, cough, the dyspnea is judged to the positive; Be judged to the positive if any one of spasm, gatism, collapse, shock, phenomena of mortality person.All are normally negative.
The result shows: two kinds of dosage forms of Qs, Qz all meet the anaphylaxis experimental standard.
Four. the mice plasma pharmacokinetic
Dosage regimen
Mice is divided into two groups at random, and fasting is 12 hours before the test, freely drinks water, difference tail vein injection clarithromycin lipide microsphere injection of the present invention (embodiment 1) and self-control reference substance solution, dosage is 15mg/Kg, respectively at 30min,, 1h, 2h, 4h, 6h, 8h, 12h, 16h gets a little, and each time point is got 6 mices.Put in the centrifuge tube of the sharp end of heparinization in advance, centrifugal, the accurate upper plasma 1000 μ L that draw after handling by certain method, get 20 μ L sample introductions, calculate the concentration of clarithromycin in each time point sample with the standard curve on the same day.Experimental result is referring to Figure of description 1.
Pharmacokinetic parameter
Average blood drug level data with 3P97 pharmacokinetics routine processes clarithromycin lipide microsphere injection of the present invention (embodiment 1) and Kelamycin injection.The result shows that the blood drug level data of clarithromycin lipide microsphere injection and Kelamycin injection all meet one-level and eliminate process.
Describe physiological disposition by blood drug level-time measured data, calculate pharmacokinetic parameter.The result shows, main pharmacokinetic parameters AUC
0-∞, AUMC
0-∞, AUC
0-t, AUMC
0-t, S
2, MRT, VRT there was no significant difference.
Show that by blood plasma pharmacokinetics result of the test in the rat body clarithromycin lipide microsphere injection of the present invention there is no obvious slow releasing function in the mice body.The clarithromycin lipide microsphere injection is similar to homemade clarithromycin solution pharmacokinetic characteristic.
Claims (4)
1. the lipide microsphere injection of a clarithromycin, in the quality of said preparation, it comprises:
Oil for injection 10%-20%,
Clarithromycin 0.1%～1%,
Surfactant 0.5%～5%,
Glycerol 0.2%～10%,
Oil phase solubilizing agent 0.2%～2%,
Metal-chelator 0.1%～1%,
Water for injection 40～90%,
Wherein:
Oil for injection is selected from safflower oil, soybean oil, Semen Maydis oil, Oleum Ricini, C7-C9 fatty acid triglycercide and composition thereof;
Surfactant is selected from lecithin, fabaceous lecithin, cholesterol, enuatrol, oleic acid, Tween 80, pluronic F68 and composition thereof;
The oil phase solubilizing agent is valeric acid, caproic acid, enanthic acid, sad, n-nonanoic acid, capric acid, oleic acid or its mixture arbitrarily;
Metal-chelator is a disodium edetate, sodium calcium edetate, or its mixture;
The particle diameter of this lipide microsphere injection is 150-260nm;
This lipide microsphere injection is to prepare by the following method:
1) clarithromycin with recipe quantity is dissolved in the oil phase solubilizing agent, mixes with the oil for injection of recipe quantity again, forms oil phase, and magnetic agitation also is heated to 30-100 ℃;
2) surfactant, metal-chelator and glycerol are dispersed in the part water for injection, magnetic agitation makes it to be uniformly dispersed, and is heated to 30-100 ℃, as water;
3) under magnetic agitation, oil phase is joined aqueous phase, add the back and continue to stir, get colostrum;
4) with the colostrum homogenate under the 15000-30000rpm condition for preparing, up to obtaining milky emulsion;
5) in this emulsion, add remaining water for injection, under 700-900bar high pressure, adopt high pressure homogenizer to carry out homogenizing; Form the microgranule of particle diameter, promptly get the lipide microsphere injection of clarithromycin of the present invention at 150-260nm.
2. according to the lipide microsphere injection of the clarithromycin of claim 1, wherein the oil phase solubilizing agent is the mixture of caproic acid, oleic acid and arbitrary proportion thereof.
3. according to the lipide microsphere injection of the clarithromycin of claim 2, it also can comprise medicinal acid or alkali.
4. according to the lipide microsphere injection of the clarithromycin of claim 3, wherein said medicinal acid is hydrochloric acid, and described alkali is sodium hydroxide.
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| IT1400415B1 (en) | 2010-05-26 | 2013-05-31 | Over S R L | COMPOSITIONS FOR THE TREATMENT OF THE HELICOBACTER PYLORI INFECTION. |
| CN104173288B (en) * | 2014-09-03 | 2017-01-18 | 沈阳药科大学 | Clarithromycin ion pair lipidosome injection and preparation method thereof |
| CN104771362B (en) * | 2014-09-03 | 2018-01-02 | 沈阳药科大学 | A kind of CLA ion pair lipide microsphere injection and preparation method thereof |
| WO2017180783A1 (en) * | 2016-04-12 | 2017-10-19 | Bio-Up Mimetic Technologies, Inc. | Re-oiled and hyper-oiled lecithin carrier vehicles |
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| 药剂学. 毕殿洲，241，人民卫生出版社. 1999 |
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