CN102266289B - Cilnidipine liposome solid preparation - Google Patents
Cilnidipine liposome solid preparation Download PDFInfo
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- CN102266289B CN102266289B CN 201110271925 CN201110271925A CN102266289B CN 102266289 B CN102266289 B CN 102266289B CN 201110271925 CN201110271925 CN 201110271925 CN 201110271925 A CN201110271925 A CN 201110271925A CN 102266289 B CN102266289 B CN 102266289B
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Abstract
The invention discloses a cilnidipine liposome solid preparation and a manufacture method thereof. By preparing cilnidipine used as an active ingredient and a specific combination of dicetyl phosphate, cholesterol, hydrogenated soybean lecithin, PEG (polyethylene glycol) 600 and Tween 40 into a liposome, the stability, dissolution and bioavailability of the drug are greatly increased, the quality of the preparation finished product is improved, the toxic and side effects of the preparation are reduced, and the preparation has a stable and lasting action and a significant curative effect.
Description
Technical field
The present invention relates to a kind of lipidosome solid preparation, be specifically related to cilnidipine lipidosome solid preparation and method for making thereof, belong to medical technical field.
Background technology
Cilnidipine (Cilnidipine), chemical name are 1,4-dihydro-2,6-dimethyl-4-(3-nitrobenzophenone)-3,5-dipicolinic acid 2-methoxyl group ethyl ester Cinoxolone, molecular formula C
27H
28N
2O
7, molecular weight 492.52, structural formula:
Cilnidipine belongs to 1, and the 4-dihydropyridine type calcium antagonists is developed by Japanese fuji Co., Ltd., and in nineteen ninety-five December in Japanese Initial Public Offering.Cilnidipine is a third generation dual pathways dihydropyridine calcium channel blocker; Except that L channel blocking effect with most of calcium channel blockers; Also act on perineural N passage, can not cause blood pressure lowering back reflection property increased heart rate and pressure receptor booster reaction, thereby become new calcium channel blocker with unique pharmacological action to acute cold stimulation; Can block flow of calcium ions; And can suppress the release of intracellular calcium, thus playing the effect of long-acting blood pressure lowering, hypotensive effect is superior to nifedipine.Clinically, cilnidipine is mainly used in hyperpietic's treatment.
The therapeutic effect of cilnidipine depends on the design to its pharmaceutical preparation to a great extent.Importantly, the form of the cilnidipine chemical compound of pro ore medicine should provide high bioavailability, reaches maximization so that cilnidipine gets into the absorption of blood, and the amount that is retained in the cilnidipine in the gastrointestinal tract reaches and minimizes.
Patent CN1709246A discloses a kind of Cilnidipine orally disintegrating tablet and preparation method thereof.Cilnidipine combines as active pharmaceutical ingredient and water soluble adjuvant, disintegrating agent and correctives in this method.
Patent CN101543483A discloses a kind of Sinetipin capsule and preparation method thereof and quality determining method, and the drug weight of its preparation consists of: 1～3 part of cilnidipine, 15～40 parts of starch, 6～20 parts of sugar, 1～5 part of cellulose.Its preparation method is: with cilnidipine, starch, sugar, cellulose pulverize separately, drying, and the method mix homogeneously that the mixed powder of cilnidipine, cellulose mixed powder and starch, lactose is increased progressively according to equivalent.
Patent CN101933915A discloses the hypertensive percutaneous dosing cilnidipine of a kind of treatment paster; It is formed by stacking gradually all-in-one-piece backing, medicine layer and adherent layer; Wherein, Described medicine layer is processed by cilnidipine, the short infiltration layer of skin and pressure sensitive adhesive, and the ratio of its weight is: 1: 0.08～0.23: 0.7～1.1.
Yet the cilnidipine preparation of method for preparing prepares though screened specific adjuvant, has certain advantage; But the dissolution of medicine and bioavailability still remain to be improved, and the long-time stability of medicine are undesirable, are unfavorable for long-term storage.
Liposome is meant drug encapsulation made spherical targeted drug carrier formulation of superminiature in the middle of the thin film that the lipoids bimolecular forms, and belongs to a kind of novel form of targeting drug delivery system.Liposome has plurality of advantages as pharmaceutical carrier: can seal fat-soluble medicine like liposome, can seal water soluble drug again; Alleviate allergy and immunoreation; Delay to discharge, reduce elimination speed in the body; Can protect the medicine that is wrapped effectively, improve bioavailability; Change medicine distribution in vivo, and can the release of targeting property, the toxic and side effects of medicine can be reduced; Be fit to multipath administration etc.
The main mechanism of action of liposome is that drug powder or solution are wrapped in the aqueous phase that the liposome bilayer lipid membrane sealed or embed in the liposome bilayer lipid membrane; This microgranule type of having cellularity; Get into the interior back of human body and activated the autoimmune function of body by reticuloendothelial system phagocytic; And change is distributed in the body of entrapped drug; Drug main to be put aside in histoorgans such as liver, spleen, lung and bone marrow, thereby improve the therapeutic index of medicine, reduce the therapeutic dose and the toxicity that reduces medicine of medicine.
If can cilnidipine be processed liposome, then be expected to overcome a series of problems that existing cilnidipine preparation exists, improve the dissolubility and the stability of medicine; Prolong drug retention time in vivo; Improve bioavailability, reduce toxic and side effects, improve treatment speed and therapeutic effect.
But, the challenge of preparation liposome is to select suitable liposome constituent and method for making.Because the character of liposome is directly closely related with the composition of liposome like stability, envelop rate, onset time, in vivo circulation time, bioavailability and toxic and side effects etc.; And the composition of liposome with the pharmaceutical properties that will seal directly closely related; Therefore, selecting which type of composition to form the cilnidipine liposome with better quality is the problem that needs to be resolved hurrily.
The applicant finds through a large amount of experiments; The lipidosome solid preparation that adopts particular excipient and cilnidipine to process has effectively overcome the problem of principal agent poor stability; Improve the dissolution of medicine simultaneously, delayed to discharge, increased medicine retention time in vivo.
Summary of the invention
The inventor is through studying discovery for a long period of time; Through cilnidipine, two Cetyl Phosphates, cholesterol, hydrogenated soya phosphatide, PEG600 and the polysorbate40 of selecting the specified weight proportioning for use; Can form the cilnidipine liposome of excellent quality; Again liposome is processed solid preparation with general formulation method, thereby accomplish the present invention.
The purpose of this invention is to provide a kind of cilnidipine liposome, it is by comprising that following materials of weight proportions composition processes:
Another object of the present invention provides the method for preparing of above-mentioned cilnidipine liposome, and this method may further comprise the steps:
(a) cilnidipine, two Cetyl Phosphates, cholesterol, hydrogenated soya phosphatide, PEG600 and polysorbate40 are dissolved in the organic solvent, stir and make its dissolving;
(b) above-mentioned solution is placed eggplant-shape bottle, organic solvent is removed in 50 ℃ of water-bath decompressions, on the bottle wall, forms uniformly transparent film;
(c) in eggplant-shape bottle, add buffer solution, continue to make the films swell hydration 50 ℃ of water-bath normal pressure rotations;
(d) with above-mentioned solution with 0.45 μ m filtering with microporous membrane, filtrating is placed-20 ℃ of refrigerator and cooled freeze and spends the night, take out to melt then, multigelation three times, spray drying makes cilnidipine liposome powder.
A purpose more of the present invention provides a kind of cilnidipine lipidosome solid preparation, and it is processed by cilnidipine liposome and other pharmaceutic adjuvants.
Wherein said cilnidipine liposome is by comprising that following materials of weight proportions composition processes:
Based on the cilnidipine of 1 weight portion, the amount of other pharmaceutic adjuvants is the 26-44 weight portion.
A purpose more of the present invention provides the method for preparing of above-mentioned cilnidipine lipidosome solid preparation, and this method may further comprise the steps:
(1) preparation of cilnidipine liposome: cilnidipine, two Cetyl Phosphates, cholesterol, hydrogenated soya phosphatide, PEG600 and polysorbate40 are prepared into the liposome powder together;
(2) preparation of cilnidipine lipidosome solid preparation: liposome powder and other pharmaceutic adjuvants are mixed with the cilnidipine lipidosome solid preparation.
Wherein, said pharmaceutic adjuvant is selected from diluent, disintegrating agent, binding agent, wetting agent, lubricant and combination thereof.
Wherein, the preparation of step (1) cilnidipine plastid preferably includes following substep:
(a) cilnidipine, two Cetyl Phosphates, cholesterol, hydrogenated soya phosphatide, PEG600 and polysorbate40 are dissolved in the organic solvent, stir and make its dissolving;
(b) above-mentioned solution is placed eggplant-shape bottle, organic solvent is removed in 50 ℃ of water-bath decompressions, on the bottle wall, forms uniformly transparent film;
(c) in eggplant-shape bottle, add buffer solution, continue to make the films swell hydration 50 ℃ of water-bath normal pressure rotations;
(d) with above-mentioned solution with 0.45 μ m filtering with microporous membrane, filtrating is placed-20 ℃ of refrigerator and cooled freeze and spends the night, take out to melt then, multigelation three times, spray drying makes cilnidipine liposome powder.
The preparation of step (2) cilnidipine liposome solid preparation preferably includes following substep:
(e) cilnidipine liposome powder and diluent, disintegrating agent and binding agent are mixed, the mix homogeneously that sieves adds wetting agent and prepares soft material, the granulation of sieving, drying;
(f) dried granule and mix lubricant is even, granulate sieves;
(g) tabletting or filled capsules make the cilnidipine lipidosome solid preparation.
Compare with existing preparation technique, cilnidipine lipidosome solid preparation provided by the invention has improved preparation dissolution, stability and bioavailability greatly; Reduce toxic and side effects, improved the formulation products quality, improved therapeutic effect.
Description of drawings
Fig. 1 is the release in vitro curve of sample among free medicine of cilnidipine and the embodiment 1-3; Wherein trunnion axis is represented 0～24 hour time; Vertical axis is represented the cumulative release percent of cilnidipine, and curve 1 is the curve of free medicine, and curve 2 is the curve of embodiment 1 sample; Curve 3 is the curve of embodiment 2 samples, and curve 4 is the curve of embodiment 3 samples.
The specific embodiment
Below further specify through specific embodiment the present invention, characteristics of the present invention and advantage will become more clear along with these explanations.
In order to form colory cilnidipine lipidosome solid preparation; Can good compatible with cilnidipine it well be sealed and non-leakage filmogen thereby importantly seek; So that form colory cilnidipine liposome; Make that the stripping property excellence and the bioavailability of this liposome are high, and seek the pharmaceutic adjuvant that can form solid preparation with the cilnidipine liposome.
To achieve these goals, big quantity research and realization that the inventor carries out find that cilnidipine, two Cetyl Phosphates, cholesterol, hydrogenated soya phosphatide, PEG600 and the polysorbate40 of specified weight proportioning can be processed the cilnidipine liposome; Wherein, Cilnidipine envelop rate as active constituents of medicine is high, and stripping property is good, the retention time significant prolongation of the active constituents of medicine in the gained solid preparation in the body circulation; Bioavailability obviously improves, and curative effect obviously improves.
On the one hand, the present invention provides a kind of cilnidipine liposome, and it is processed by the supplementary material composition that comprises following weight proportion:
Preferably, the present invention provides a kind of cilnidipine liposome, and it is processed by the supplementary material composition that comprises following weight proportion:
As the phospholipid that is used to form liposome, it is of a great variety, and commonly used have natural phospholipid and a synthetic phospholipid.Natural phospholipid comprises cupreol, Phosphatidylserine, PHOSPHATIDYL ETHANOLAMINE, Ovum Gallus domesticus Flavus lecithin, hydrogenation egg yolk lecithin, EPG, egg yolk lecithin acyl serine, egg yolk lecithin acyl inositol, soybean lecithin, hydrogenated soya phosphatide, soybean phospholipid acyl glycerol, soy phosphatidylserine and soybean phospholipid acyl inositol etc.Synthetic phospholipid comprises stearmide, dioleoyl phospholipid phatidylcholine, distearyl acid phosphatidylcholine, dipalmitoyl phosphatidyl choline, two myristoyl phosphatidylcholines, two Laurel phosphatidyl cholines, DOPG, distearyl phosphatidyl glycerol, two palmityl phosphatidyl glycerols, GLYCEROL,DIMYRISTOYL PHOSPHATIDYL, two lauroyl phosphatidyl glycerols etc.
The inventor is through long-term conscientious research; Through a large amount of screening tests; Find to adopt this area phospholipid commonly used and additives for the cilnidipine liposome of film material preparation under the accelerated test of 40 ℃ of high temperature, relative humidity 75% ± 5%, stable and envelop rate is not good.
The inventor is through studying discovery for a long period of time, and the film material of two Cetyl Phosphates of appropriate amount, cholesterol and hydrogenated soya phosphatide combination can be used to form colory cilnidipine liposome.Can form the suitably high liposome of envelop rate of size, appropriate configuration composition through the method that provides among the present invention, and two Cetyl Phosphates make cilnidipine non-leakage in formed liposome, and the stripping property of cilnidipine is excellent in the liposome.If use consumption as two Cetyl Phosphates beyond the preferable range, perhaps select other phospholipid material such as lecithin etc. for use, then the poor stability of formed liposome, envelop rate is low, stripping property is poor, can not realize the object of the invention.
In cilnidipine liposome of the present invention, for the cilnidipine of 1 weight portion, the consumption of two Cetyl Phosphates is the 15-25 weight portion.If the consumption of two Cetyl Phosphates is lower than 15 weight portions respectively, have a large amount of free cilnidipines and do not sealed, the drug loading of liposome is low, and stability also can descend, and stripping property also can affect adversely; Otherwise the consumption of two Cetyl Phosphates is higher than 25 weight portions, and then the envelop rate as the cilnidipine of active constituents of medicine descends.
Hydrogenated soya phosphatide stability is fine, combines with two Cetyl Phosphates and cholesterol, can stop the cohesion of crystal structure.Hydrogenated soya phosphatide mixes the duplicature of two Cetyl Phosphates and cholesterol formation, is similar to " buffer agent " and equally plays the effect of regulating membrane structure " flowability ", and liposome stability is significantly strengthened.
In cilnidipine liposome of the present invention, cholesterol, PEG600 and polysorbate40 are used to regulate the membrane stability and the permeability of liposome.
Cholesterol is a kind of amphiphilic, combines with two Cetyl Phosphates, stops it to be condensed into crystal structure.Cholesterol mixes in the duplicature of two Cetyl Phosphates formation, is similar to " buffer agent " and equally plays the effect of regulating membrane structure " flowability ".When being lower than phase transition temperature, cholesterol can make film reduce ordered arrangement, increases mobile; When being higher than phase transition temperature, cholesterol can increase the ordered arrangement of film, thereby reduces the flowability of film.Cholesterol can make liposome bimolecular tunic solidify, thereby reduces the generation of free radical, reduces oxidation level, and liposome stability is significantly strengthened.
The inventor is through discovering, when the weight ratio of two Cetyl Phosphates and cholesterol is 15-25: during 8-14, can form stable cilnidipine liposome.When the weight ratio of two Cetyl Phosphates and cholesterol is higher than 15-25: during 8-14, membrane stability reduces; When the weight ratio of two Cetyl Phosphates and cholesterol is lower than 15-25: during 8-14, the liposome membrane flowability is too high, is wrapped in the intravital cilnidipine of lipid and is easy to discharge.
In addition, discover that when the weight of two Cetyl Phosphates and cholesterol is 15-25: during 8-14, formed liposome stripping property is excellent.
Research shows that the stability of liposome and stripping property and bioavailability have close corresponding relation.Stability is high more, and dissolution is good more, and bioavailability is high more.Therefore, the stability of cilnidipine liposome of the present invention is high, dissolution is excellent, is to cause one of high factor of drug bioavailability.
In addition; The inventor discovers; In cilnidipine liposome of the present invention, for the cilnidipine of 1 weight portion, the consumption of two Cetyl Phosphates is that the consumption of 15-25 weight portion, cholesterol is that the consumption of 8-14 weight portion, hydrogenated soya phosphatide is the 15-25 weight portion; The weight ratio of two Cetyl Phosphates and cholesterol is 15-25: 8-14: during 15-25, the envelop rate of formed cilnidipine liposome is high.
In cilnidipine liposome of the present invention, use polysorbate40 further to improve the stability and the envelop rate of liposome membrane.Polysorbate40 is a kind of non-ionic surface active agent, when being used for the duplicature of two Cetyl Phosphates formation, can not only further improve the dissolubility of cilnidipine, thereby improve envelop rate; And can improve the chemical energy between this duplicature, thus the chemical stability of liposome in waterborne liquid improved, and then improve the stability of cilnidipine liposome.
In cilnidipine liposome of the present invention, for the cilnidipine of 1 weight portion, the consumption of polysorbate40 is the 5-10 weight portion.If the consumption of polysorbate40 is lower than 5 weight portions; Then cause improving not enough to the stability and the envelop rate of liposome owing to its consumption is low excessively; Otherwise if the consumption of polysorbate40 is higher than 10 weight portions, it is too high and cause liposome membrane to be easy to destroy and reveal active component then to be used for its consumption.
In cilnidipine liposome of the present invention; An amount of proportioning through cholesterol and polysorbate40 has the collaborative facilitation of regulating to two Cetyl Phosphate membrane structures, can form envelop rate height, stable high cilnidipine liposome, and its dissolution is excellent; Had good sustained release effect, bioavailability is high.
Bound by theory not; The inventor is surprisingly found out that; Adding PEG600 can change the pharmaceutical properties of cilnidipine liposome, and Macrogol 600 has certain viscosity and surface activity effect, can reduce the surface tension between liposome and the gastrointestinal tract mucus; Promote medicine to get into gastrointestinal mucosa, thereby improve bioavailability and therapeutic effect.The inventor finds that PEG600 is superior to other Polyethylene Glycol such as PEG400 or PEG800.In liposome of the present invention, for the cilnidipine of 1 weight portion, the consumption of PEG600 is 5-15 part, and consumption is crossed and low then stability, envelop rate and the release of liposome improved inadequately, and its consumption is too high also to can not get the good liposome of expecting.
On the other hand, the present invention provides the method for preparing of cilnidipine liposome, and this method may further comprise the steps:
(a) cilnidipine, two Cetyl Phosphates, cholesterol, hydrogenated soya phosphatide, PEG600 and polysorbate40 are dissolved in the organic solvent, stir and make its dissolving;
(b) above-mentioned solution is placed eggplant-shape bottle, organic solvent is removed in 50 ℃ of water-bath decompressions, on the bottle wall, forms uniformly transparent film;
(c) in eggplant-shape bottle, add buffer solution, continue to make the films swell hydration 50 ℃ of water-bath normal pressure rotations;
(d) with above-mentioned solution with 0.45 μ m filtering with microporous membrane, filtrating is placed-20 ℃ of refrigerator and cooled freeze and spends the night, take out to melt then, multigelation three times, spray drying makes cilnidipine liposome powder.
In an embodiment preferred of cilnidipine method for preparing lipidosome of the present invention; Organic solvent described in the step (a) is selected from one or more in ethanol, chloroform, dichloromethane, n-butyl alcohol, isopropyl alcohol, acetone, the benzene tert-butyl alcohol, the normal hexane, is preferably dichloromethane.
In a preferred embodiment of cilnidipine lipidosome solid preparation method for preparing of the present invention; Buffer salt solution described in the substep (c) is selected from a kind of in phosphate buffer, citrate buffer, acetate buffer, borate buffer solution and the carbonate buffer solution, and preferred pH value is 6.8 phosphate buffer (its preparation can referring to the pharmacopeia appendix).
Through said method, can prepare the little and uniform cilnidipine liposome of particle size distribution of granule, its envelop rate is high, and stability is high, and stripping property is good, and bioavailability is high.
Discover that the size of liposome is to influence the liposome principal element with the time of staying that distributes in vivo, the particle diameter of liposome is more little, and the time of staying is long more in the body.Cilnidipine liposome particles through the inventive method preparation is little, and particle size distribution is even, and this is one of its factor that metabolic rate is low in vivo, bioavailability is high.
On the one hand, the present invention provides the cilnidipine lipidosome solid preparation again, and it is processed by cilnidipine liposome and other pharmaceutic adjuvants.
Wherein said cilnidipine liposome is processed by the supplementary material composition that comprises following weight proportion:
Based on the cilnidipine of 1 weight portion, the amount of other pharmaceutic adjuvants is the 26-44 weight portion.
In an embodiment preferred of cilnidipine lipidosome solid preparation of the present invention, the cilnidipine liposome is processed by the supplementary material composition that comprises following weight proportion:
In this article; The meaning of used term " other pharmaceutic adjuvants " or " pharmaceutic adjuvant " and excipient equivalent in meaning; Be meant the medicinal material except the cilnidipine liposome that uses in order to prepare the cilnidipine lipidosome solid preparation, comprise diluent, disintegrating agent, binding agent, wetting agent, lubricant and combination thereof.
In this article, used term " amounts of other pharmaceutic adjuvants " is meant the weight sum of above-mentioned pharmaceutic adjuvant.
The consumption of various pharmaceutic adjuvants can be selected according to the general consumption of each adjuvant in solid preparation by those skilled in the art, and this is in those skilled in the art's limit of power.
In an embodiment preferred of cilnidipine lipidosome solid preparation of the present invention, said diluent is selected from one or more in starch, lactose, Icing Sugar, amylum pregelatinisatum, sorbitol, microcrystalline Cellulose, the dextrin, is preferably starch and sorbitol.
In an embodiment preferred of cilnidipine lipidosome solid preparation of the present invention; Said disintegrating agent is selected from one or more in low-substituted hydroxypropyl cellulose, carboxymethyl starch sodium, cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone, the dried starch, preferred polyvinylpolypyrrolidone.
In an embodiment preferred of cilnidipine lipidosome solid preparation of the present invention; Said binding agent is selected from a kind of in 30 POVIDONE K 30 BP/USP 30, starch slurry, hypromellose, sodium carboxymethyl cellulose, ethyl cellulose, arabic gum, the xanthan gum, is preferably sodium carboxymethyl cellulose.
In an embodiment preferred of cilnidipine lipidosome solid preparation of the present invention, said wetting agent is the alcoholic solution of 10-80%, preferred 30% alcoholic solution.
In an embodiment preferred of cilnidipine lipidosome solid preparation of the present invention; Said lubricant is selected from one or more in magnesium stearate, zinc stearate, sodium laurylsulfate, Pulvis Talci, micropowder silica gel, Macrogol 4000, the stearic acid, is preferably zinc stearate.
Cilnidipine lipidosome solid preparation provided by the invention is an oral formulations, comprises tablet and capsule.
In practice, consider the effective dose of medicine and the convenience of medication, in the preferred embodiment of cilnidipine lipidosome solid preparation of the present invention, the specification of preparation is that per unit preparation cilnidipine is 5mg, 10mg.
On the one hand, the present invention provides the method for preparing of above-mentioned cilnidipine lipidosome solid preparation again, and this method may further comprise the steps:
(1) preparation of cilnidipine liposome: cilnidipine, two Cetyl Phosphates, cholesterol, hydrogenated soya phosphatide, PEG600 and polysorbate40 are prepared into the liposome powder together;
(2) preparation of cilnidipine lipidosome solid preparation: liposome powder and other pharmaceutic adjuvants are mixed with the cilnidipine lipidosome solid preparation.
Wherein, said pharmaceutic adjuvant is selected from diluent, disintegrating agent, binding agent, wetting agent, lubricant and combination thereof.
In a preferred implementation of the method for preparing of cilnidipine liposome solid preparation, the preparation of step (1) cilnidipine plastid comprises following substep:
(a) cilnidipine, two Cetyl Phosphates, cholesterol, hydrogenated soya phosphatide, PEG600 and polysorbate40 are dissolved in the organic solvent, stir and make its dissolving;
(b) above-mentioned solution is placed eggplant-shape bottle, organic solvent is removed in 50 ℃ of water-bath decompressions, on the bottle wall, forms uniformly transparent film;
(c) in eggplant-shape bottle, add buffer solution, continue to make the films swell hydration 50 ℃ of water-bath normal pressure rotations;
(d) with above-mentioned solution with 0.45 μ m filtering with microporous membrane, filtrating is placed-20 ℃ of refrigerator and cooled freeze and spends the night, take out to melt then, multigelation three times, spray drying makes cilnidipine liposome powder.
In a preferred embodiment of cilnidipine lipidosome solid preparation method for preparing of the present invention; Organic solvent described in the substep (a) is selected from one or more in ethanol, chloroform, dichloromethane, n-butyl alcohol, isopropyl alcohol, acetone, the benzene tert-butyl alcohol, the normal hexane, is preferably dichloromethane.
In a preferred embodiment of cilnidipine lipidosome solid preparation method for preparing of the present invention; Buffer salt solution described in the substep (c) is selected from a kind of in phosphate buffer, citrate buffer, acetate buffer, borate buffer solution and the carbonate buffer solution, and preferred pH value is 6.8 phosphate buffer.
In an embodiment preferred of cilnidipine lipidosome solid preparation method for preparing of the present invention, the preparation of step (2) cilnidipine liposome solid preparation comprises following substep:
(e) cilnidipine liposome powder and diluent, disintegrating agent and binding agent are mixed, the mix homogeneously that sieves adds wetting agent and prepares soft material, the granulation of sieving, drying;
(f) dried granule and mix lubricant is even, granulate sieves;
(g) tabletting, filled capsules or pack make the cilnidipine lipidosome solid preparation.
In the method for the invention, can also sterilize to liposome and/or lipidosome solid preparation as required.Sterilizing methods does not have specific (special) requirements, can use liposome sterilizing methods commonly used in the pharmaceutical field, like filtration sterilization, radiation sterilization or sterile working etc.
The present invention becomes liposome through the active component cilnidipine with the combined preparation of the specified weight of two Cetyl Phosphates, cholesterol, hydrogenated soya phosphatide, PEG600 and polysorbate40 earlier, is mixed and made into solid preparation with other pharmaceutic adjuvant again.Gained solid preparation product quality is high, and particle diameter is even, and stability is high, and envelop rate is high, and dissolution is good, and medicine retention time in blood circulation is long, and is evident in efficacy, reduced toxic and side effects.
The method for preparing of cilnidipine lipidosome solid preparation provided by the invention has improved product quality, and equipment is simple, easy operating, and method is simple, is suitable for industrialized great production.
In this article, if not explanation especially, content or consumption are all by weight.
Embodiment
Below through concrete preferred embodiment the present invention is further specified.These embodiment only are illustrative, and should not be construed as limitation of the present invention.
Embodiment 1 cilnidipine liposome sheet
Used supplementary material is following:
Adopt following production technology to prepare cilnidipine liposome sheet:
(1) 5g cilnidipine, 125g two Cetyl Phosphates, 70g cholesterol, 125g hydrogenated soya phosphatide, 75gPEG600 and 50g polysorbate40 are dissolved in the 1000ml dichloromethane, stir and make its dissolving;
(2) above-mentioned solution is placed eggplant-shape bottle, dichloromethane is removed in 50 ℃ of water-bath decompressions, on the bottle wall, forms uniformly transparent film;
(3) in eggplant-shape bottle, adding 1000ml pH is 6.8 phosphate buffer, continues to make the films swell hydration 50 ℃ of water-bath normal pressures rotations;
(4) with above-mentioned solution with 0.45 μ m filtering with microporous membrane, filtrating is placed-20 ℃ of refrigerator and cooled freeze and spends the night, take out to melt then, multigelation three times, spray drying makes cilnidipine liposome powder.
(5) with cilnidipine liposome powder and 150g starch, 50g sorbitol and 10g polyvinylpolypyrrolidone and the mixing of 8g sodium carboxymethyl cellulose, cross 80 mesh sieve mix homogeneously, add the ethanol preparation soft material of 80ml 30%, the granulation of sieving, drying;
(6), cross 20 mesh sieve granulate with dried granule and 2g zinc stearate mix homogeneously;
(7) tabletting makes 1000 cilnidipine liposome sheets.
Embodiment 2 cilnidipine liposome sheets
Used supplementary material is following:
Adopt following production technology to prepare cilnidipine liposome sheet:
(1) 10g cilnidipine, 200g two Cetyl Phosphates, 120g cholesterol, 200g hydrogenated soya phosphatide, 100gPEG600 and 80g polysorbate40 are dissolved in the 2000ml dichloromethane, stir and make its dissolving;
(2) above-mentioned solution is placed eggplant-shape bottle, dichloromethane is removed in 50 ℃ of water-bath decompressions, on the bottle wall, forms uniformly transparent film;
(3) in eggplant-shape bottle, adding 2000ml pH is 6.8 phosphate buffer, continues to make the films swell hydration 50 ℃ of water-bath normal pressures rotations;
(4) with above-mentioned solution with 0.45 μ m filtering with microporous membrane, filtrating is placed-20 ℃ of refrigerator and cooled freeze and spends the night, take out to melt then, multigelation three times, spray drying makes cilnidipine liposome powder.
(5) with cilnidipine liposome powder and 200g starch, 100g sorbitol and 15g polyvinylpolypyrrolidone and the mixing of 10g sodium carboxymethyl cellulose, cross 80 mesh sieve mix homogeneously, add the ethanol preparation soft material of 100ml 30%, the granulation of sieving, drying;
(6), cross 20 mesh sieve granulate with dried granule and 5g zinc stearate mix homogeneously;
(7) tabletting makes 1000 cilnidipine liposome sheets.
Embodiment 3 cilnidipine liposome methods
Used supplementary material is following:
Adopt following production technology to prepare the cilnidipine liposome methods:
(1) 10g cilnidipine, 150g two Cetyl Phosphates, 80g cholesterol, 150g hydrogenated soya phosphatide, 50gPEG600 and 50g polysorbate40 are dissolved in the 2000ml ethanol, stir and make its dissolving;
(2) above-mentioned solution is placed eggplant-shape bottle, ethanol is removed in 50 ℃ of water-bath decompressions, on the bottle wall, forms uniformly transparent film;
(3) in eggplant-shape bottle, adding 1000ml pH is 6.8 phosphate buffer, continues to make the films swell hydration 50 ℃ of water-bath normal pressures rotations;
(4) with above-mentioned solution with 0.45 μ m filtering with microporous membrane, filtrating is placed-20 ℃ of refrigerator and cooled freeze and spends the night, take out to melt then, multigelation three times, spray drying makes cilnidipine liposome powder.
(5) with cilnidipine liposome powder and 150g starch, 80g sorbitol and 15g polyvinylpolypyrrolidone and the mixing of 13g sodium carboxymethyl cellulose, cross 80 mesh sieve mix homogeneously, add the ethanol preparation soft material of 100ml 30%, the granulation of sieving, drying;
(6), cross 20 mesh sieve granulate with dried granule and 2g zinc stearate mix homogeneously;
(7) filled capsules makes 1000 cilnidipine liposome methods.
Comparative Examples 1-3
Adopt with embodiment 1-3 in step (1)～(4) prepare the identical production technology of cilnidipine liposome powder, the supplementary material composition in will the Comparative Examples 1-3 shown in following table 1 is processed cilnidipine liposome powder respectively:
Table 1 Comparative Examples is formed
Wherein, "/" expression is not used.
The mensuration of Test Example 1 envelop rate
Be taken in the step (4) of embodiment 1-3 with Comparative Examples 1-3 in the cilnidipine liposome powder 1g of gained be dissolved in the 10ml water, suspension, get suspension 0.5mL; Be added on SephadexG-50 gel column top, with the phosphate buffer eluting, flow velocity 1ml/min; Collect 4～11mL eluent (containing liposome); Blow to the about 0.5ml of volume with nitrogen, add the dehydrated alcohol breakdown of emulsion and be settled to 10ml, shake up.The accurate 10ul solution of drawing, sample introduction is measured peak area, the content of the cilnidipine that calculating lipid body weight is sealed; Precision is measured cilnidipine liposome turbid liquor 0.5ml in addition, is settled to 10mL with dehydrated alcohol, shakes up.The accurate 10ul solution of drawing, the total amount of cilnidipine in the mensuration liposome turbid liquor.Computational envelope rate, result are shown in the following table 2:
The mensuration result of table 2 envelop rate
Can know that by table 2 compare with the liposome in the comparative example, the envelop rate of cilnidipine liposome of the present invention will exceed a lot.
Can know that through comparing embodiment 1-3 and Comparative Examples 1-3 liposome of the present invention has higher envelop rate.This shows that the envelop rate of cilnidipine liposome is directly related with the composition kind that is used to form liposome.When the composition beyond the used composition of use the present invention, the envelop rate of gained cilnidipine liposome is starkly lower than the present invention.Also the consumption with each composition that is used to form liposome is relevant in addition.
The size and the particle size distribution of Test Example 2 liposome particle diameters
In order to understand cilnidipine liposome particle size parameters and particle size distribution accurately; Be taken in the embodiment 1-3 step (4) with Comparative Examples 1-3 in an amount of liposome powder of gained, directly use laser particle size analyzer (Easysizer20, American-European gram company) to observe its outward appearance; And mensuration particle diameter; Handle with the dynamic light scattering process software, the distribution of measuring its diameter and calculating particle diameter, the result is shown in the following table 3:
Table 3 liposome particle diameter
Can be known that by table 3 mean diameter of gained liposome is little more a lot of than the mean diameter of gained liposome among the Comparative Examples 1-3 among the embodiment of the invention 1-3, and the size homogeneous, outward appearance is better.
Can know that with Comparative Examples 1-3 liposome of the present invention has littler mean diameter through comparing embodiment 1, particle size distribution is more even, and outward appearance is better.This shows that the particle diameter of cilnidipine liposome is relevant with each composition and the consumption thereof that are used to form liposome.When the composition beyond the used composition of use the present invention, the character such as mean diameter, particle size distribution and outward appearance of gained cilnidipine liposome obviously are inferior to the present invention.
Existing research shows, liposome particles size and the degree of being evenly distributed and its envelop rate and stability and relevant in the intravital time of staying of people, and liposome particles is more little, particle size distribution is even more; Its envelop rate and stability are high more, the time of staying in the human recycle system longer (referring to novel pharmaceutical formulation, front page; The 18 chapter; The 408-468 page or leaf, Zhu Shengshan chief editor, Chemical Industry Press).The document is introduced here as a reference in full.
Therefore, little, the particle size distribution of cilnidipine liposome mean diameter of the present invention evenly is a factor that further promotes excellent performances such as its envelop rate, stability, retention time time length in vivo, bioavailability.
Test Example 3 stability and dissolution are investigated
40 ℃ of high temperature, following 6 months of relative humidity 75% ± 5% condition is carried out the accelerated test investigation with the cilnidipine sheet (Bengbu FengYuan TuShan Pharmaceutical Co., Ltd, lot number H20100731) of the sample of above embodiment 1-3 preparation and listing, and the result sees table 4.
Table 4 stability and dissolution determination result
Can be known that by table 4 the cilnidipine sheet dissolution of listing is low, content reduces obviously when quickening June, and related substance raises; And the sample dissolution for preparing among the embodiment of the invention 1-3 is high, quickens that content and related substance all do not have significant change after 6 months.Proved absolutely the superiority of the present invention aspect raising stability and dissolution.
Test Example 4 release in vitro researchs
Precision take by weighing the middle gained of step (4) among the free medicine of cilnidipine and the embodiment 1-3 each 1g of liposome powder (amount with cilnidipine is as the criterion) be dissolved in the 10ml water; Getting each 2ml of suspension places bag filter to tighten; Release medium is PBS (containing 0.25% the polysorbas20) 100ml of pH 6.8, and bath temperature is 37 ℃, and speed of agitator is 100rpm; Respectively at 0.5,1,2,4,6,8,12,18, the 24h 1ml that takes a sample; Measure release rate, draw release profiles, shown in result such as the accompanying drawing 1.
Wherein, the free medicine of curve 1 expression, the sample of curve 2 expression embodiment 1, the sample of curve 3 expression embodiment 2, the sample of curve 4 expression embodiment 3.
The result shows that the free medicine rate of release of cilnidipine is fast, reaches more than 93% in 4 hours; And the release of gained cilnidipine lipidosome solid preparation is slow among the embodiment of the invention 1-3, just reaches release in about 92%, 18 hour fully, and has reached the effect of slow release in 18 hours.
Industrial applicibility
Result by the foregoing description and experimental example can know that cilnidipine lipidosome solid preparation of the present invention has good surface appearance, and granule is little; Particle diameter is even, and envelop rate is high, and stability is high; Stripping property is good, and percolation ratio is low, and the time of staying in vivo is long; Bioavailability is high, has the favorable industrial using value.
More than through the specific embodiment and embodiment the present invention is specified; But should understand; These explanations do not constitute any restriction to scope of the present invention; Under the situation that does not depart from spirit of the present invention and protection domain, can carry out multiple modification, improvement and replacement to technical scheme of the present invention and embodiment thereof, these are all because of falling in protection scope of the present invention.
Each list of references of mentioning among the application or quoting is incorporated herein by reference at this in full.
Claims (9)
1. cilnidipine liposome, it is processed by the supplementary material composition that comprises following weight proportion:
2. cilnidipine liposome according to claim 1, it is processed by the supplementary material composition that comprises following weight proportion:
3. the method for preparing of claim 1 or 2 described cilnidipine liposomees, this method may further comprise the steps:
(a) cilnidipine, two Cetyl Phosphates, cholesterol, hydrogenated soya phosphatide, PEG600 and polysorbate40 are dissolved in the organic solvent, stir and make its dissolving;
(b) above-mentioned solution is placed eggplant-shape bottle, organic solvent is removed in 50 ℃ of water-bath decompressions, on the bottle wall, forms uniformly transparent film;
(c) in eggplant-shape bottle, add buffer solution, continue to make the films swell hydration 50 ℃ of water-bath normal pressure rotations;
(d) with above-mentioned solution with 0.45 μ m filtering with microporous membrane, filtrating is placed-20 ℃ of refrigerator and cooled freeze and spends the night, take out to melt then, multigelation three times, spray drying makes cilnidipine liposome powder.
4. method according to claim 3, wherein, the organic solvent described in the step (a) is selected from a kind of in ethanol, chloroform, dichloromethane, n-butyl alcohol, the isopropyl alcohol;
It is 6.8 phosphate buffer that buffer salt solution described in the step (c) is selected from pH value.
5. cilnidipine lipidosome solid preparation, it is processed with other pharmaceutic adjuvants by claim 1 or 2 described cilnidipine liposomees, and based on the cilnidipine of 1 weight portion, the amount of other pharmaceutic adjuvants is the 26-44 weight portion.
6. cilnidipine lipidosome solid preparation according to claim 5, it is tablet or capsule.
7. method for preparing according to claim 5 or 6 said cilnidipine lipidosome solid preparations, this method may further comprise the steps:
(1) preparation of cilnidipine liposome: cilnidipine, two Cetyl Phosphates, cholesterol, hydrogenated soya phosphatide, PEG600 and polysorbate40 are prepared into the liposome powder together;
(2) preparation of cilnidipine lipidosome solid preparation: liposome powder and other pharmaceutic adjuvants are mixed with the cilnidipine lipidosome solid preparation.
8. method according to claim 7, wherein the preparation of step (1) cilnidipine liposome comprises following substep:
(a) cilnidipine, two Cetyl Phosphates, cholesterol, hydrogenated soya phosphatide, PEG600 and polysorbate40 are dissolved in the organic solvent, stir and make its dissolving;
(b) above-mentioned solution is placed eggplant-shape bottle, organic solvent is removed in 50 ℃ of water-bath decompressions, on the bottle wall, forms uniformly transparent film;
(c) in eggplant-shape bottle, add buffer solution, continue to make the films swell hydration 50 ℃ of water-bath normal pressure rotations;
(d) with above-mentioned solution with 0.45 μ m filtering with microporous membrane, filtrating is placed-20 ℃ of refrigerator and cooled freeze and spends the night, take out to melt then, multigelation three times, spray drying makes cilnidipine liposome powder;
Wherein, the organic solvent described in the step (a) is selected from a kind of in ethanol, chloroform, dichloromethane, n-butyl alcohol, the isopropyl alcohol;
It is 6.8 phosphate buffer that buffer salt solution described in the step (c) is selected from pH value.
9. method according to claim 7, wherein, the preparation of step (2) cilnidipine lipidosome solid preparation comprises following substep:
(e) cilnidipine liposome powder is mixed with diluent, disintegrating agent and binding agent, the mix homogeneously that sieves adds wetting agent and prepares soft material, the granulation of sieving, drying;
(f) dried granule and mix lubricant is even, granulate sieves;
(g) tabletting or filled capsules make the cilnidipine lipidosome solid preparation.
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