CN101199505A - Verapamil liposome and preparing method thereof - Google Patents
Verapamil liposome and preparing method thereof Download PDFInfo
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Abstract
The invention discloses verapamil liposome and a preparation method of the verapamil liposome, belonging to the technical field of medicine. The verapamil liposome is composed of verapamil, phospholipid, cholesterol, chitosan, cationic lipid and antioxidant, etc., all of which are in certain weight percentage. The verapamil liposome is prepared by adopting ammonium sulphate gradients method, film hydration method, ethanol injection method and reverse phase evaporation method. The invention adopts chitosan or derivatives of the chitosan to modify the surface of the liposome, and applies the chitosan to ophthalmic preparation, which can further increase corneal retention of the liposome and can remarkably improve the corneal penetration amount of the drug, with obvious advantages compared with ordinary liposome. With high entrapment efficiency, good stability, good biocompatibility, biological adhesiveness and biodegradability, the prepared liposome can realize sustained release and long-acting administration, particularly suitable for administration on ocular region, and can better play the ocular effects of anti-glaucoma and anti-cataract of verapamil.
Description
Technical field:
The present invention relates to field of pharmaceutical preparations, be specifically related to verapamil liposome and preparation method thereof.
Background technology:
Verapamil is an aralkyl amine calcium antagonist, by regulating the flow of calcium ions on myocardium transfer cell, myocardial contraction cell and the vascular smooth muscle cell film, brings into play its pharmacotoxicological effect, but does not change serum calcium cancentration.Verapamil is usually used in treating variant angina pectoris, unstable angina pectoris, chronic stable angina pectoris; Ventricular Rate when share control Chronic Atrial Fibrillation and/or atrial flutter with digoxin; The outbreak repeatedly of prevention paroxysmal supraventricular tachycardia; Essential hypertension.
Along with to the deepening continuously of its pharmaceutical research, the clinical practice of verapamil is also extensive day by day.As: treatment bronchial asthma, liver cirrhosis, migraine, mania etc.In recent years, found its pharmacological action, and come into one's own gradually, mainly contained eye:
1. glaucoma: studies confirm that verapamil can effectively reduce the glaucoma patient intraocular pressure.Abelson etc. suffer from glaucoma to 15 examples and do not accept the verapamil hydrochloride 40 μ L of the local eye drip 0.125% of volunteer of any treatment, check behind the 30min and find that ophthalmic has been pressed with significant decline, studies show that further this effect can continue 10 hours.Goya1 etc. discover, three times/d, 0.125% verapamil hydrochloride solution of totally two all local eye drips can reduce the intraocular pressure of glaucoma patient constantly, and very little to the reduction effect of systemic blood pressure.
2. anti-cataract: verapamil is as a kind of Ca
2+Channel blocker can stop Ca in the aqueous humor
2+Enter in the crystalline lens, thereby can effectively reduce Ca
2+In crystalline intravital accumulation, stop or delay Ca
2+The metabolism disorder of piling up and causing alleviates cataractous generation and development, is expected to become the cataractous new drug of treatment.Ettl etc. studies confirm that 0.2% verapamil hydrochloride eye drop can effectively suppress the cataractous development of diabetes type.Studies show that the interior calcium ion of crystalline lens, magnesium ion and the iron concentration that the rat skin lower injection verapamil can prevent that radiation from causing of Bardak etc. raise, and the cataract that the prompting verapamil causes radiation has potential protective effect.Zhong Yisheng etc. have studied the effect of verapamil in galactose cataract formation and development process, and the result shows that the subcutaneous injection verapamil can suppress the formation of lenticular opacity, and has reduced Ca in the crystalline lens
2+Content.Wang Xiangqun etc. studies show that, verapamil has blocking effect to the cataract that dexamethasone brings out.
Other: except that cataract and glaucoma, calcium antagonists such as verapamil hydrochloride are at control proliferative vitreoretinopathy (proliferative vitreoretinopathy, PVR), also shown than wide prospect in the special experimentation of sending out property blepharospasm, central retinal artery occlusion and ocular tumor, will more and more be used in field of ophthalmology.
Because the special physiological structure of human eye, behind the ordinary eye drops eye drip loss very big, under the souring of tear, run off rapidly, retention time is a few minutes only, bioavailability is very low, generally is no more than 5%.And the dose that can cause whole body to absorb during long-term, frequent drug administration increases, and side effect increases.
In order to improve the defective of conventional local eye drip preparation, and the research of having risen dosing eyes system (OcularDrug Delivery System), it focuses on making medicine to have slow, controlled release and long-acting, increases the cornea permeability of medicine, increase bioavailability, reduce side effect etc.
For glaucoma and cataractous treatment, require can effectively see through cornea behind the medicine eye drip, in aqueous humor, reach certain treatment concentration.And glaucoma and the cataractous process of preventing and treating are longer, need long term administration.Therefore require drug-supplying system to have slow release and long-acting, reduce the eye drip number of times as far as possible, reduce systemic side effects and the zest of eye.In sum, verapamil dosing eyes system should have following three characteristics at least: the cornea permeability that 1) increases medicine; 2) action time of prolong drug, reduce medicine frequency; 3) nontoxic nonirritant.
Liposome is as new drug carrier, is the research focus in medicament field in recent years, has extremely strong actual application value.Liposome is as pharmaceutical carrier, can: (1) strengthens the dissolubility of medicine; (2) lower drug toxicity; (3) give drug targeting; (4) slow releasing function of increase medicine; (5) the protection medicine improves stability of drug; (6) by the film fusion medicine is sent into cell interior, realize administration in the cell.In recent years, liposome receives publicity day by day as the research and the application of the carrier of eye medicinal.Liposome release mechanism is unique, can make medicine see through corneal epithelial cell by fusion.Liposome can play the effect of drug-reservoir, realizes slow release and long-acting administration, and liposome has certain bioadhesive, can increase the time of contact of medicine and cornea, so the cornea that helps medicine sees through; In particular, liposome has good biocompatibility and degradability, to the nontoxic nonirritant of part tissue of eye, does not influence the normal physiological function of eye, is outstanding dosing eyes system.Therefore, verapamil is made liposome eye drops, can realize the slow release and the long-acting of medicine, reduce the medication number of times, reduce the fluctuation of drug level, improve bioavailability of medicament, reduce the toxic and side effects of medicine, improve patient's compliance.Chinese patent CN1206987C is prepared into liposome eye drops with the NSAID (non-steroidal anti-inflammatory drug) indomethacin, has significantly reduced the burning sensation and the sensation of pricking of eye behind the eye drip, and curative effect is better than common indomethacin eye drop.
Chitosan is natural cation polysaccharide, has excellent biological compatibility and biodegradability, has to be used for the dosing eyes systematic research.When chitosan is used for dosing eyes, have good biomembrane adhesion and infiltration promotion property.Use chitosan that surface of liposome is modified, can be in conjunction with the advantage of the two, bring into play the characteristics of film amalgamation, slow-releasing and the bigger drug loading of chitosan unique biological adhesion, anatonosis and liposome simultaneously, therefore, chitosan-modified verapamil liposome is with respect to conventional liposome, have higher bioavailability, can bring into play the eye treatment effect of medicine better.
Summary of the invention:
The purpose of this invention is to provide a kind of verapamil liposome and preparation method thereof with slow release and long-acting.
Verapamil liposome of the present invention contains following component and percentage by weight:
Verapamil 0.01%-50.00%
Phosphatidase 11 0.00%-99.99%
Cholesterol 0.00%-65.00%
Chitosan 0.00%-89.99%
Chitosan derivatives 0.00%-89.99%
Cation lipid 0.00%-89.99%
Antioxidant 0.00%-40.00%.
Verapamil liposome of the present invention, wherein verapamil can be any in racemic modification (RS-) verapamil, left-handed (S-) verapamil and dextrorotation (R-) verapamil, or wherein any hydrochlorate, lactate, sulfate, nitrate, citrate, maleate, tartrate or bitartrate etc.
Verapamil liposome of the present invention, wherein phospholipid can be natural origin, synthetic, the artificial semi-synthetic or manually modified phospholipid substance that two fat hydrocarbon chains respectively contain 8 to 26 saturated or unsaturated carbon atoms, can be soybean lecithin, hydrogenated soy phosphatidyl choline, Ovum Gallus domesticus Flavus lecithin, hydrogenated yolk lecithin, phosphatidylcholine, PHOSPHATIDYL ETHANOLAMINE, Phosphatidylserine, phosphatidyl glycerol, phosphatidylinositols or alkyl ether phosphatidylcholine etc., or wherein any derivant.Derivant can be polyethyleneglycol modified phospholipid etc., for example Macrogol 2000-DSPE (PEG2000-DSPE).A kind of or any several mixture in the above-mentioned phospholipid of optional usefulness prepares verapamil liposome.
Verapamil liposome of the present invention can use chitosan or chitosan derivatives that surface of liposome is coated or modifies.
Verapamil liposome of the present invention; wherein cation lipid can be stearmide, 18-amine., 2; 3-two oleoyl oxygen propyl group-1-bromination trimethylamine (DOTMA), 1; the trimethylammonio propane of 2-two oleoyls-3-(DOTAP), GERBU Adjuvant 100 (DDAB) or N ', N '-dimethylaminoethyl-3-carbamyl cholesterol (DC-Chol) etc.Optional usefulness above-mentioned any one or any several mixture.
Verapamil liposome of the present invention, wherein antioxidant is hydroquinone, Hydroxycoumarin, vitamin E, vitamin C, citric acid, malic acid, ascorbyl palmitate, gallic acid alkane ester, BHA (BHA), fourth hydroxy-methylbenzene (BHT), nordihydroguaiaretic acid, sodium sulfite, sodium sulfite, sodium pyrosulfite or sodium thiosulfate etc.Optional usefulness above-mentioned any one or any several mixture.
Verapamil liposome of the present invention can further add osmotic pressure regulator, and osmotic pressure regulator is: sodium chloride, glucose, mannitol, sorbitol, xylitol, glycerol, hyaluronic acid sodium or hyaluronic acid etc.Optional usefulness above-mentioned any one or any several mixture.
Verapamil liposome of the present invention; can further be prepared into eye drop or injection; and can add freeze drying protectant (excipient) and further be prepared into lyophilized formulations, wherein freeze drying protectant (excipient) is sucrose, lactose, glucose, trehalose, maltose, mannitol, sorbitol, mannitol or leucine etc.Optional usefulness above-mentioned any one or any several mixture.
Verapamil liposome of the present invention, can further be prepared into gel, wherein gel-type vehicle is carbomer (carbomer), poloxamer (Poloxamer), hypromellose (HPMC), alginate, ethyl cellulose, methylcellulose, carboxymethyl cellulose, glycerol, propylene glycol, chitosan, agar, tragakanta, gelatin or starch etc.Optional usefulness above-mentioned any one or any several mixture.
The preparation method of verapamil liposome of the present invention is as follows:
One, the preparation of liposome: verapamil liposome can make by following four kinds of methods:
1. ammonium sulphate gradient: phospholipid, cholesterol, sodium deoxycholate and the antioxidant of recipe quantity are dissolved in the small amount of ethanol, slowly be injected in the certain density ammonium sulfate under uniform temperature, the magnetic agitation, the insulation certain hour makes the ethanol volatilization fully, ultrasonic or even matter is handled, and promptly gets blank liposome.The gained blank liposome is placed bag filter, and tighten at two ends, places the ammonium sulfate of the outer aqueous phase of a certain amount of aqueous phase dialysis weeding of grease plastid.The blank liposome that dialysis is good continues the insulation certain hour under uniform temperature, under agitation add a certain amount of verapamil aqueous solution, adjusts final volume, promptly.
2. film dispersion method: verapamil, phospholipid, cholesterol, sodium deoxycholate and the antioxidant of getting recipe quantity, with an amount of organic solvent dissolution, place round-bottomed flask, rotary evaporation is removed organic solvent under certain condition, make it on the bottle wall, to form even, the exsiccant thin film of one deck, inflated with nitrogen, vacuum drying spends the night.The gained thin film adds a certain amount of water, abundant under certain condition aquation, and ultrasonic or even matter is handled, promptly.
3. alcohol injection: verapamil, phospholipid, cholesterol, sodium deoxycholate and the antioxidant of recipe quantity are dissolved in the small amount of ethanol, slowly be injected in the certain density ammonium sulfate under uniform temperature, the magnetic agitation, the insulation certain hour makes the ethanol volatilization fully, ultrasonic or even matter is handled, promptly.
4. reverse phase evaporation: phospholipid, cholesterol, sodium deoxycholate and the antioxidant of recipe quantity are dissolved in an amount of ether, the verapamil of recipe quantity is dissolved in an amount of aqueous phase.With the two mixing, violent jolting, ultrasonicly make it to form w/o type Emulsion, pour in the round-bottomed flask, rotary evaporation under certain condition is carefully controlled evaporation rate, when mixture reaches heavy-gravity colloidal state, add an amount of water again, continue rotary evaporation and remove remaining ether, ultrasonic or even matter is handled, promptly.
Two, the chitosan or derivatives thereof is to the coating of liposome:
The chitosan or derivatives thereof is soluble in water under certain condition, a certain amount of this drips of solution is added in the verapamil liposome suspension for preparing, under agitation, adjust the pH value to 7.0 of system, continue to stir promptly.
Verapamil liposome of the present invention, when making eye drop, the drug level of its recommendation is 2.5mg/mL; When making injection, the drug level of its recommendation is 5mg/mL.
The present invention uses the chitosan or derivatives thereof that surface of liposome is modified, and be applied to ophthalmic preparation, can further increase the cornea anelasticity of liposome, significantly improve the cornea transit dose of medicine, having remarkable advantages with respect to conventional liposome, is the dosing eyes system that has very much practical value.
The verapamil liposome that the present invention developed, its envelop rate can reach 99.7%, and particle size distribution is even, can reach intravenous injection or local medicinal standard.It has good stability, and 4 ℃ of following inflated with nitrogen store, and internal stability was good in 6 months, and its envelop rate, particle diameter and outward appearance all do not have significant change, and can further improve its stability by making dried frozen aquatic products.Simultaneously, blank liposome of the present invention-ammonium sulphate gradient medicine carrying preparation technology is fit to industrialized great production very much, and boundless industrialization prospect is arranged.
Animal experiment study is the result show, verapamil liposome of the present invention, have slow release and long-acting, can improve bioavailability of medicament, reduce the fluctuation of drug level, therefore can bring into play effects such as the glaucoma of verapamil and anti-cataract well, have remarkable advantages than ordinary eye drops.Zoopery is specific as follows:
1. rabbit isolated cornea permeability experiment
Purpose: the cornea permeability of research ophthalmic preparation.
Animal: New Zealand white rabbit, body weight 2.5-3.0kg, male and female are not limit.
Reagent: verapamil liposome (embodiment 1), verapamil chitosan coat liposome (embodiment 2), verapamil normal saline solution (2.5mg/mL).
Method: adopting the vertical diffusion cell of improved Franz is experimental provision, and as shown in Figure 1, it is by supply pool and accept the pond and forms, internal diameter 0.90cm, effective diffusion area 0.70cm
2, accept pond 7.8mL.Rabbit auricular vein injection air is put to death, isolated cornea immediately, place the supply pool of diffusion cell and accept between the pond, accept to fill in the pond glutathion-sodium bicarbonate Ringer's solution as dispersive medium, add test sample 2mL in the supply pool, place 34 ℃ of constant temperature blender with magnetic force, take a sample in different time points, sample is behind 0.22 μ m filtering with microporous membrane, and HPLC measures, and calculates the accumulative total transit dose.
The result: experimental result is seen Fig. 2.The cornea transit dose of verapamil is that chitosan coats liposome＞liposome＞eye drop in 6 hours, prove that liposome of the present invention can effectively promote the cornea permeability of verapamil, make more medicine see through cornea and arrive aqueous humor, improve the concentration of medicine in aqueous humor, thereby bring into play drug effect better.
2. rabbit is tested in body cornea anelasticity
Purpose: the adhesion of research ophthalmic preparation corneal.
Animal: New Zealand white rabbit, body weight 2.5-3.0kg, male and female are not limit.
Reagent: verapamil liposome (embodiment 1), verapamil chitosan coat liposome (embodiment 2), verapamil normal saline solution (2.5mg/mL).
Method: during administration, rabbit is fixed, draw back eyelid gently and make and the eyeball pouch, splash into liposome or eye drop 150 μ L with micro sample adding appliance respectively, decontrol palpebra inferior more gently, medicine can not overflowed.After the administration, in different time points, (5mm * 2mm) places that the fornix place is sticking under the tame lagophthalmos conjunctival sac gets tear, weigh immediately after the taking-up (the tear volume is tried to achieve by the weight difference before and after the sampling of filter paper bar) with the quantitative filter paper article of having weighed.: the filter paper bar is put in the centrifuge tube, adds methanol 0.5mL, and supersound extraction 15min is centrifugal, gets supernatant, and HPLC measures behind the 0.22 μ m filtering with microporous membrane, calculates the drug level in the different time points tear.
The result: experimental result is seen Fig. 3.The result shows that in 3 hours, the size order of the cornea anelasticity of medicine is that chitosan coats liposome＞liposome＞eye drop, has proved that liposome and chitosan corneal have the effect of sticking.This effect of sticking can reduce preparation and wash away the loss that causes at eye owing to tear, thereby improves bioavailability, and brings into play long-acting and slow releasing function.
3. the microdialysis method is measured clear-headed rabbit aqueous humor Chinese medicine concentration
Purpose: the adhesion of research ophthalmic preparation corneal.
Animal: New Zealand white rabbit, body weight 2.5-3.0kg, male and female are not limit.
Reagent: verapamil liposome (embodiment 1), verapamil chitosan coat liposome (embodiment 2), verapamil normal saline solution (2.5mg/mL).
Method: the microdialysis probe underwent operative is implanted among the lagophthalmos anterior chamber,, promptly begun to carry out the pharmacokinetics experiment through 2 day convalescent period.With the normal saline is infusion liquid, flow velocity 3.0 μ Lmin
-1, behind the flushing 0.5h, in conjunctival sac, splashing into 150 μ L preparations, the every 10min of initial 40min collects sample, and every afterwards 20min collects sample, and sample carries out HPLC to be measured, and calculates the mean drug concentration in the aqueous humor in the different time sections.
Result: the results are shown in Table 1.In 6 hours, liposome and chitosan coat the peak concentration (C of liposome
Max) be respectively 1.22 times of eye drop with 1.55 times, area under curve (AUC) be respectively 1.47 times of eye drop with 2.08 times, the peak time (T of medicine
Max) be longer than eye drop.The relative bioavailability that liposome and chitosan coat liposome is respectively 146.7% and 207.7%, and has slow release and long-acting.
Table 1 microdialysis method is measured verapamil pharmacokinetic parameters (n=6, mean ± SD) in clear-headed rabbit aqueous humor
| Sample | C max/μg·mL -1 | T max/min | AUC/μ g·mL -1·min | Relative bioavailability |
| Eye drop liposome chitosan coats liposome | 0.317±0.043 0.388±0.065* 0.490±0.081** | 43.33±8.16 63.33±8.16 90.00±10.95 | 60.78±11.42 89.16±14.72** 126.22±18.30** | - 146.7％ 207.7％ |
* P＜0.05, * *, P＜0.01, with the eye drop group relatively
Above-mentioned experiment shows, verapamil is made liposome, and it is coated with chitosan, can effectively promote the cornea permeability of verapamil, improve the concentration of medicine in aqueous humor, meanwhile, the effect of sticking of liposome and chitosan corneal can reduce preparation and wash away the loss that causes at eye owing to tear, thereby the raising bioavailability, and bring into play long-acting and slow releasing function.Therefore can reduce the medication number of times, reduce the fluctuation of drug level, improve drug effect.And chitosan coats liposome and has significant advantage with respect to the liposome that does not coat.
Verapamil liposome of the present invention can be used for approach such as eye usefulness, intravenous injection and transdermal administration, especially the eye time spent, can improve the cornea transit dose of medicine, improve bioavailability of medicament, reduce the toxic and side effects of medicine, realize slow release and long-acting, reduce the medication number of times, reduce the fluctuation of drug level, therefore can bring into play effects such as the glaucoma of verapamil and anti-cataract better.
Liposome of the present invention not only is suitable for verapamil, and is also applicable for other anti-glaucoma medicines and anti-cataract medicine as ideal ocular drug carrier, or as valuable reference.
The present invention makes liposome with verapamil first, at present, there is no the report of verapamil liposome at home and abroad, more do not have the listing of related preparations, so the present invention has actual application prospect and the potential economic worth that attracts people's attention.
Description of drawings: Fig. 1 is the vertical diffusion cell sketch map of improved Franz.1 is supply pool among the figure, and 2 is cornea, and 3 for accepting the pond, and 4 is stirrer, and 5 is sample tap.
Fig. 2 is verapamil liposome (2.5mg/mL) rabbit isolated cornea penetration curve, is contrast (n=3) with the eye drop.
Fig. 3 be verapamil liposome (2.5mg/mL) rabbit at body cornea anelasticity curve, be contrast (n=3) with the eye drop.
Fig. 4 measures verapamil at clear-headed rabbit aqueous humor Chinese medicine concentration-time curve (n=6) for the microdialysis method.
The specific embodiment:
Verapamil hydrochloride 25mg
Phosphatidylcholine 120mg
18-amine. 5mg
Cholesterol 50mg
Preparation method: phospholipid, cholesterol and the 18-amine. of recipe quantity are dissolved in the 4mL ethanol, slowly be injected in the 8mL 0.125mol/L ammonium sulfate under 50 ℃, magnetic agitation, 50 ℃ of insulated and stirred 1h make the ethanol volatilization fully, put the ultrasonic 5min of probe in the ice bath, promptly get blank liposome.The gained blank liposome is placed bag filter, and tighten at two ends, puts the 24h that dialyses in the 1000mL 0.9%NaCl solution, the ammonium sulfate of the outer aqueous phase of weeding of grease plastid.The blank liposome that dialysis is good under agitation slowly adds the aqueous solution that 1mL contains the 25mg verapamil hydrochloride in 60 ℃ of insulations down, continues insulation 20min, regulates final volume to 10mL with 0.9%NaCl solution, promptly gets the verapamil hydrochloride liposome.
Verapamil hydrochloride 25mg
Phosphatidylcholine 120mg
18-amine. 5mg
Cholesterol 50mg
Chitosan 10mg
Preparation method: phospholipid, cholesterol and the 18-amine. of recipe quantity are dissolved in the 4mL ethanol, slowly be injected in the 8mL 0.125mol/L ammonium sulfate under 50 ℃, magnetic agitation, 50 ℃ of insulated and stirred 1h make the ethanol volatilization fully, put the ultrasonic 5min of probe in the ice bath, promptly get blank liposome.The gained blank liposome is placed bag filter, and tighten at two ends, puts the 24h that dialyses in the 1000mL 0.9%NaCl solution, the ammonium sulfate of the outer aqueous phase of weeding of grease plastid.The blank liposome that dialysis is good under agitation slowly adds the aqueous solution that 1mL contains the 25mg verapamil hydrochloride in 60 ℃ of insulations down, continues insulation 20min, promptly gets the verapamil hydrochloride liposome.Chitosan is dissolved in the 1mL pH6.0 acetum, under magnetic agitation, this solution is joined in the verapamil hydrochloride liposome, and regulates pH to 7.0 with 0.1MNaOH solution, promptly gets the verapamil hydrochloride liposome that chitosan coats.
Verapamil hydrochloride 50mg
Phosphatidylcholine 300mg
PEG2000-DSPE 10mg
Cholesterol 100mg
Preparation method: verapamil hydrochloride, phospholipid, PEG2000-DSPE and the cholesterol of getting recipe quantity are with the 5mL dissolve with ethanol, slowly be injected in the 10mL 0.9%NaCl solution under 50 ℃, magnetic agitation, 50 ℃ of insulated and stirred 30min make the ethanol volatilization fully, put the ultrasonic 5min of probe in the ice bath, promptly.
Verapamil hydrochloride 50mg
Phosphatidylcholine 300mg
Sodium deoxycholate 100mg
Vitamin E 10mg
Preparation method: phospholipid, sodium deoxycholate and the vitamin E of recipe quantity are dissolved in the 10mL ether; The verapamil hydrochloride of recipe quantity is dissolved in the 5mL pH7.4 phosphate buffer water in getting.With the two mixing, violent jolting, ultrasonicly make it to form w/o type Emulsion, pour in the 50mL round-bottomed flask, in 30 ℃ of following rotary evaporations, when mixture reaches heavy-gravity colloidal state, add 5mL pH7.4 phosphate buffer again, continue at 30 ℃ of following rotary evaporation 30min, put the ultrasonic 5min of probe in the ice bath, promptly.
Verapamil hydrochloride 75mg
Dipalmitoyl phosphatidyl choline 400mg
Cholesterol 20mg
Vitamin E 10mg
Chitosan 10mg
Preparation method: get verapamil hydrochloride, phospholipid, cholesterol and the vitamin E of recipe quantity,, place the 100mL round-bottomed flask with the 20mL dissolve with ethanol, 45 ℃ of rotary evaporations are removed ethanol, make it on the bottle wall, to form even, the exsiccant thin film of one deck, inflated with nitrogen, vacuum drying spends the night.In round-bottomed flask, add 9mL 0.9%NaCl solution,, make thin film fully come off, soak, put the ultrasonic 5min of probe in the ice bath at 45 ℃ of following aquation 4h.Chitosan is dissolved in the 1mL pH6.0 acetum, under magnetic agitation, this solution is joined in the above-mentioned liposome, and regulates pH to 7.0 with 0.1M NaOH solution, promptly.
Claims (9)
1. verapamil liposome, it is characterized in that: its component and percentage by weight are as follows:
Verapamil 0.01%-50.00%
Phosphatidase 11 0.00%-99.99%
Cholesterol 0.00%-65.00%
Chitosan 0.00%-89.99%
Chitosan derivatives 0.00%-89.99%
Cation lipid 0.00%-89.99%
Antioxidant 0.00%-40.00%.
2. verapamil liposome according to claim 1, it is characterized in that: described verapamil is any in racemic modification verapamil, left-handed verapamil and the d-Verapamil, or wherein any hydrochlorate, lactate, sulfate, nitrate, citrate, maleate, tartrate and bitartrate.
3. verapamil liposome according to claim 1, it is characterized in that: described phospholipid is the natural origin that two fat hydrocarbon chains respectively contain 8 to 26 saturated or unsaturated carbon atoms, synthetic, artificial semi-synthetic or manually modified phospholipid substance, be selected from soybean lecithin, hydrogenated soy phosphatidyl choline, Ovum Gallus domesticus Flavus lecithin, hydrogenated yolk lecithin, phosphatidylcholine, PHOSPHATIDYL ETHANOLAMINE, Phosphatidylserine, phosphatidyl glycerol, phosphatidylinositols, in the alkyl ether phosphatidylcholine one or more, or one or more of wherein any derivant.
4. verapamil liposome according to claim 1 is characterized in that: use chitosan or chitosan derivatives that surface of liposome is coated or modifies.
5. verapamil liposome according to claim 1; it is characterized in that: described cation lipid is stearmide, 18-amine., 2; 3-two oleoyl oxygen propyl group-1-bromination trimethylamine, 1; the trimethylammonio propane of 2-two oleoyls-3-, GERBU Adjuvant 100, N ', one or more in N '-dimethylaminoethyl-3-carbamyl cholesterol.
6. verapamil liposome according to claim 1 is characterized in that: described antioxidant is one or more in hydroquinone, Hydroxycoumarin, vitamin E, vitamin C, citric acid, malic acid, ascorbyl palmitate, gallic acid alkane ester, BHA, fourth hydroxy-methylbenzene, nordihydroguaiaretic acid, sodium sulfite, sodium sulfite, sodium pyrosulfite, the sodium thiosulfate.
7. verapamil liposome according to claim 1, it is characterized in that: also can add osmotic pressure regulator, osmotic pressure regulator is: one or more in sodium chloride, glucose, mannitol, sorbitol, xylitol, glycerol, hyaluronic acid sodium, the hyaluronic acid.
8. verapamil liposome according to claim 1 is characterized in that: this liposome can further be made eye drop or injection, or adds gel-type vehicle and make gel, or the above two are added freeze drying protectant makes freeze-dried products.
9. the preparation method of a verapamil liposome as claimed in claim 1, it is characterized in that: method is ammonium sulphate gradient, film dispersion method, alcohol injection and reverse phase evaporation.
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| CN104688689A (en) * | 2015-02-11 | 2015-06-10 | 青岛大学附属医院 | Natamycin cationic liposome eye drop and preparation method thereof |
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