CN102302453A - Paroxetine hydrochloride liposome solid preparation - Google Patents
Paroxetine hydrochloride liposome solid preparation Download PDFInfo
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- CN102302453A CN102302453A CN 201110271970 CN201110271970A CN102302453A CN 102302453 A CN102302453 A CN 102302453A CN 201110271970 CN201110271970 CN 201110271970 CN 201110271970 A CN201110271970 A CN 201110271970A CN 102302453 A CN102302453 A CN 102302453A
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Abstract
The invention discloses a paroxetine hydrochloride liposome solid preparation and a preparation method thereof. According to the invention, an active component paroxetine hydrochloride and a specific composition of hydrogenated ovolecithin, cholesterol, hydrogenated soybean phospholipids, tween 40 and PEG600 are prepared into a liposome. Therefore, the dissolution rate, the stability and the bioavailability of the medicine are greatly improved. The effect of the medicine is released smoothly, and the effect is long-lasting. The curative effect of the medicine is substantial. With the preparation, the quality of the preparation product is improved, and toxic and side-effects are reduced.
Description
Technical field
The present invention relates to a kind of lipidosome solid preparation, be specifically related to paroxetine hydrochloride lipidosome solid preparation and method for making thereof, belong to the pharmaceutical preparations technology field.
Background technology
Paroxetine hydrochloride is white or off-white color crystalline powder, and odorless, bitter in the mouth are soluble in methanol; In ethanol, dissolve, slightly soluble in water, its chemical name is: (-)-anti--4-(4-fluorophenyl)-3-{[3; 4-(methylenedioxy group) phenoxy group] methyl }-piperidine hydrochlorate, molecular formula: C
19H
20NO
3FHCl, molecular weight: 365.84, structural formula is:
Paroxetine hydrochloride is developed by the U.S., and it is a selectivity nervus centralis serotonin reuptake inhibitor, can make that 5-hydroxy tryptamine concentration increases in the synaptic space, the performance antidepressant effect.A little less than other mediator effect, less to the unify influence of cardiovascular system of autonomic nerve system.
The oral easy absorption of paroxetine hydrochloride is not subjected to the influence of antiacid medicine or food, oral 30mg, and reaching the peak concentration time is 6.3h, and peak concentration is 17.6ug/ml, and T1/2 is 24h, and apparent branch is long-pending to be 3-28L/kg.Plasma protein binding rate is 95%.7-14 reaches Cpss in day, and is distributed to each histoorgan rapidly, and at liver metabolism, about 2% with original shape discharge from urine, and all the other are then discharged from urine with the metabolite form, and fraction is from defecate.Clinically be used to treat depression.Also can treat obsession, panic disorder or social anxiety disorder.
The marketed drug preparation that with the paroxetine hydrochloride is active constituents of medicine now is mainly tablet.The paroxetine hydrochloride disintegration of tablet time is long, and dissolution and dissolution rate are low, absorption difference, and bioavailability is low, has influenced the performance of paroxetine hydrochloride clinical treatment effect.
WO9520964A discloses a kind of combination of oral medication that contains paroxetine resin coordination compound, to shelter the bitterness of paroxetine.WO9703670A discloses a kind of paroxetine controlled release compositions, to reduce the side effect of paroxetine oral tablet.WO9926625A discloses the paroxetine preparation of solubilising, to improve its dissolubility.Only if WO9520964A discloses paroxetine in waterless operation, otherwise can the pulverize redness.CN1568987A discloses a kind of paroxetine hydrochloride drop pill, though pill occurred, the bioavailability each side is improved, and with respect to our the present lipidosome solid preparation of doing, its long-time stability and toxic and side effects all have much room for improvement.CN1853631A discloses the fast disintegrant of the paroxetine that contains the coating taste masking.WO2006033505A discloses the paroxetine cholate of paroxetine derivatization or cholic acid derivative salts and has comprised paroxetine and the compositions of cholic acid or chlolic acid derivatives.CN101143136A discloses a kind of paroxetine slow release micropills preparation; It is characterized in that: described preparation contains polymeric slow releasing composition; Comprise: the label that contains the paroxetine of treatment effective dose and/or preventive dose; And the micropill that is applied to said label; It partly covers the surface of this label, slowly dissolving in liquid, aqueous.CN101371836A discloses a kind of gentle slow release compositions of time-delay that contains paroxetine or its salt that pharmaceutically is suitable for, and it is characterized in that said composition is a kind of at the oral enteric sustained-release composition that slowly discharges through quilt behind the stomach.More than these preparations still have various deficiencies.
The main mechanism of action of liposome is 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 has a type cellularity; Get into the interior back of human body and activated the autoimmune function of body by reticuloendothelial system phagocytic; Distributed in the body of entrapped drug thereby change; Drug main will be put aside in histoorgans such as spleen, liver, lung and bone marrow; Thereby improve the therapeutic index of medicine, reduce the therapeutic dose and the toxicity that reduces medicine of medicine.
If paroxetine hydrochloride can be processed liposome; Then be expected to overcome a series of problems that existing paroxetine hydrochloride preparation exists; Improve the dissolubility and the stability of medicine; Prolong drug retention time in vivo; Improve bioavailability; Improve the formulation products quality, reduced toxic and side effects, improved treatment speed and therapeutic effect.
But the preparation liposome need be selected suitable liposome constituent and method for making, and this need carry out a large amount of experiment sievings and have certain degree of difficulty.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 is directly closely related with the character of the entrapped drug of wanting; So selecting which type of composition to form the paroxetine hydrochloride liposome with better quality is the problem that needs to be resolved hurrily.
We are through a large amount of research experiments; Be surprisingly found out that; The lipidosome solid preparation that adopts particular excipient and paroxetine hydrochloride to process; Can further improve the stability of principal agent effectively; Improve the dissolution of medicine simultaneously; Delay the release of medicine, increase medicine retention time in vivo.
Summary of the invention
The inventor is through discover in a large number; Through paroxetine hydrochloride, hydrogenated yolk lecithin, cholesterol, hydrogenated soya phosphatide, polysorbate40 and the PEG600 that selects the specified weight proportioning for use; Can form the paroxetine hydrochloride 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 paroxetine hydrochloride liposome, it is processed by the supplementary material composition that comprises following weight proportion:
Condition is: hydrogenated yolk lecithin: cholesterol: the weight ratio of hydrogenated soya phosphatide is 3～4: 1: 2～3; Hydrogenated yolk lecithin preferably: cholesterol: the weight ratio of hydrogenated soya phosphatide is 3: 1: 2.
Another object of the present invention provides the method for preparing of above-mentioned paroxetine hydrochloride liposome, and this method may further comprise the steps:
(a) paroxetine hydrochloride, hydrogenated yolk lecithin, cholesterol, hydrogenated soya phosphatide, polysorbate40 and PEG600 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 46 ℃ 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 46 ℃ 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 paroxetine hydrochloride liposome powder.
A further object of the present invention provides a kind of paroxetine hydrochloride lipidosome solid preparation, and it is processed by paroxetine hydrochloride liposome (intermediate products) and other pharmaceutic adjuvants,
Wherein said paroxetine hydrochloride liposome is processed by the supplementary material composition that comprises following weight proportion:
Condition is: based on the paroxetine hydrochloride of a weight ratio, hydrogenated yolk lecithin: cholesterol: the weight ratio of hydrogenated soya phosphatide is 3～4: 1: 2～3; Hydrogenated yolk lecithin preferably: cholesterol: the weight ratio of hydrogenated soya phosphatide is 3: 1: 2.
Preferably, paroxetine hydrochloride: hydrogenated yolk lecithin: cholesterol: the weight ratio of hydrogenated soya phosphatide is 1: 3: 1: 2.
Preferably, wherein said paroxetine hydrochloride liposome is processed by the supplementary material composition that comprises following weight proportion:
Based on the paroxetine hydrochloride of 1 weight portion, the amount of other pharmaceutic adjuvants is the 1-3.5 weight portion.
A further object of the present invention provides the method for preparing of above-mentioned paroxetine hydrochloride lipidosome solid preparation, and this method may further comprise the steps:
(1) preparation of paroxetine hydrochloride liposome: paroxetine hydrochloride, hydrogenated yolk lecithin, cholesterol, hydrogenated soya phosphatide, polysorbate40 and PEG600 are prepared into the liposome powder together;
(2) preparation of paroxetine hydrochloride lipidosome solid preparation: liposome powder and other pharmaceutic adjuvants are mixed with the paroxetine hydrochloride 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) paroxetine hydrochloride plastid preferably includes following substep:
(a) paroxetine hydrochloride, hydrogenated yolk lecithin, cholesterol, hydrogenated soya phosphatide, polysorbate40 and PEG600 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 46 ℃ 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 46 ℃ 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 paroxetine hydrochloride liposome powder.
The preparation of step (2) paroxetine hydrochloride liposome solid preparation preferably includes following substep:
(e) paroxetine hydrochloride liposome powder and diluent, disintegrating agent and binding agent are mixed, the mix homogeneously that sieves adds wetting agent and prepares soft material, the preparation that sieves, drying;
(f) dried granule and mix lubricant is even, granulate sieves;
(g) tabletting makes the paroxetine hydrochloride lipidosome solid preparation.
Compare with existing ordinary preparation, paroxetine hydrochloride 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, improved clinical safety in utilization.
Description of drawings
Fig. 1 is the release in vitro curve of listing Comparative formulation and embodiment 1-3 sample, and wherein trunnion axis is represented 0～24 hour time, and vertical axis is represented the cumulative release percent of paroxetine hydrochloride.Wherein, the release profiles of curve 1 expression listing Comparative formulation, the release profiles of curve 2 expression embodiment 1 sample, the release profiles of curve 3 expression embodiment 2 samples, the release profiles of curve 4 expression embodiment 3 samples.
The specific embodiment
Through the specific embodiment the present invention is further specified, characteristics of the present invention and advantage more clearly are described.
In order to obtain colory paroxetine hydrochloride lipidosome solid preparation; Thereby important is to seek good compatible with paroxetine hydrochloride it well to be sealed and non-leakage material; Be convenient to form colory paroxetine hydrochloride liposome; Make that the stripping property excellence and the bioavailability of this liposome are high, and seek the relative best pharmaceutic adjuvant that can form solid preparation with the paroxetine hydrochloride liposome.
To achieve these goals; Big quantity research and test that the inventor carries out; The paroxetine hydrochloride liposome that paroxetine hydrochloride, hydrogenated yolk lecithin, cholesterol, hydrogenated soya phosphatide, polysorbate40 and the PEG600 of discovery specified weight proportioning can process; Wherein, Paroxetine hydrochloride envelop rate as active constituents of medicine is high, and stripping property is good, and the retention time of the active constituents of medicine in the gained solid preparation in the body circulation is long; Bioavailability is high, and curative effect is high.
On the one hand, the present invention provides a kind of paroxetine hydrochloride liposome, and it is processed by the supplementary material composition that comprises following weight proportion:
Condition is: hydrogenated yolk lecithin: cholesterol: the weight ratio of hydrogenated soya phosphatide is 3～4: 1: 2～3; Hydrogenated yolk lecithin preferably: cholesterol: the weight ratio of hydrogenated soya phosphatide is 3: 1: 2.
Preferably, paroxetine hydrochloride liposome provided by the invention 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 Ovum Gallus domesticus Flavus lecithin, Phosphatidylserine, PHOSPHATIDYL ETHANOLAMINE, 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 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 studies; Through a large amount of screening tests; Find to adopt paroxetine hydrochloride liposome that single phospholipid commonly used and additives prepare for the film material under the accelerated test of 40 ℃ of high temperature, relative humidity 75% ± 5%; Stability and envelop rate are not good, and percolation ratio is up to more than 30%.
Research shows that the stability of liposome and stripping property and bioavailability have close corresponding relation.Stability is high more, and stripping property is good more, and bioavailability is high more.Therefore, the stability of paroxetine hydrochloride liposome of the present invention is high, stripping property is excellent, is to cause one of high factor of drug bioavailability.
The inventor is through conscientiously discover the hydrogenated yolk lecithin of appropriate amount: cholesterol for a long time: hydrogenated soya phosphatide is with weight ratio 3～4: the film materials of 1: 2～3 combinations can be used to form colory paroxetine hydrochloride liposome.Can form suitably size, well-balanced through the method that provides among the present invention; The liposome that the envelop rate of appropriate configuration composition is high; And these compositions, especially paroxetine hydrochloride are non-leakage in formed liposome, and the stripping property of paroxetine hydrochloride is excellent in the liposome.If use consumption to be hydrogenated yolk lecithin: cholesterol: hydrogenated soya phosphatide weight ratio 3～4: the scope beyond 1: 2～3; Perhaps select other phospholipid material such as Phosphatidylserine 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 paroxetine hydrochloride liposome of the present invention; For the paroxetine hydrochloride of 1 weight portion; The consumption of hydrogenated yolk lecithin is the 0.75-3 weight portion, and the consumption of cholesterol is the 0.25-1 weight portion, and the weight ratio of hydrogenated yolk lecithin and cholesterol is 3～4: 1.If the consumption of hydrogenated yolk lecithin and cholesterol is lower than 0.75 weight portion and 0.25 weight portion respectively, have a large amount of free paroxetine hydrochlorides 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 hydrogenated yolk lecithin and cholesterol is higher than 3 weight portions and 1 weight portion respectively, and then the envelop rate as the paroxetine hydrochloride of active constituents of medicine also can descend.
Hydrogenated soya phosphatide stability is fine, combines with hydrogenated yolk lecithin and cholesterol, can stop the cohesion of crystal structure.Hydrogenated soya phosphatide mixes the duplicature of hydrogenated yolk lecithin and cholesterol formation, is similar to " buffer agent " and equally plays the effect of regulating membrane structure " flowability ", and liposome stability is significantly strengthened.
The inventor is through discovering, when hydrogenated yolk lecithin: cholesterol: the weight ratio of hydrogenated soya phosphatide is 3～4: in the time of 1: 2～3, can form stable paroxetine hydrochloride liposome.When the weight ratio of hydrogenated soya phosphatide less than 2 the time, membrane stability reduces; When the weight ratio of hydrogenated soya phosphatide greater than 3 the time, liposome membrane is mobile uncomfortable, is wrapped in the intravital paroxetine hydrochloride of lipid and is easy to seepage.
In paroxetine hydrochloride liposome of the present invention, PEG600 and polysorbate40 are used to regulate the membrane stability and the permeability of liposome.
In paroxetine hydrochloride 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 hydrogenated yolk lecithin and cholesterol combination phospholipid formation, can not only further improving the dissolubility of paroxetine hydrochloride, 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 paroxetine hydrochloride liposome.
In paroxetine hydrochloride liposome of the present invention, for the paroxetine hydrochloride of 1 weight portion, the consumption of polysorbate40 is the 0.6-1 weight portion.If the consumption of polysorbate40 is lower than 0.6 weight portion; 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 1 weight portion, it is too high and cause liposome membrane to be easy to destroy and reveal active component then to be used for its consumption.
Bound by theory not; The inventor is surprisingly found out that; Adding PEG600 can change the pharmaceutical properties of paroxetine hydrochloride liposome; 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.After deliberation, the inventor finds that PEG600 is better than other Polyethylene Glycol such as PEG400 or PEG800.In paroxetine hydrochloride liposome of the present invention; For the paroxetine hydrochloride of 1 weight portion; The consumption of PEG600 is 0.75-2 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.
In paroxetine hydrochloride liposome of the present invention; Polysorbate40 and PEG600 through an amount of proportioning have collaborative regulating action to the immobilized artificial membrane structure that hydrogenated yolk lecithin, cholesterol, hydrogenated soya phosphatide make up; Can form envelop rate height, stable high paroxetine hydrochloride liposome; Its stripping property is excellent; Had good sustained release effect, bioavailability is high.
On the other hand, the present invention provides the method for preparing of paroxetine hydrochloride liposome, and this method may further comprise the steps:
(a) paroxetine hydrochloride, hydrogenated yolk lecithin, cholesterol, hydrogenated soya phosphatide, polysorbate40 and PEG600 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 46 ℃ 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 46 ℃ 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 paroxetine hydrochloride liposome powder.
In an embodiment preferred of paroxetine hydrochloride 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, methanol, n-butyl alcohol, isopropyl alcohol, acetone, benzyl alcohol, the tert-butyl alcohol, the normal hexane, preferred volume ratio be 3: 1 for ethanol and isopropyl alcohol mixed solvent.
In an embodiment preferred of paroxetine hydrochloride method for preparing lipidosome of the present invention; Buffer salt solution described in the step (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 7.0 phosphate buffered solution.For example phosphoric acid-sodium hydrogen phosphate buffer, potassium dihydrogen phosphate-dipotassium hydrogen phosphate, sodium dihydrogen phosphate-sodium hydrogen phosphate, acetic acid-sodium acetate buffer solution, citric acid-sodium citrate buffer solution preferably are 7.0 phosphate buffered solution like the pH value of pharmacopeia record.
Through said method, can prepare the little and uniform paroxetine hydrochloride 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.Paroxetine hydrochloride 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 paroxetine hydrochloride lipidosome solid preparation again, and it is processed by paroxetine hydrochloride liposome and other pharmaceutic adjuvants, and wherein said paroxetine hydrochloride liposome is processed by the supplementary material composition that comprises following weight proportion:
Condition is: hydrogenated yolk lecithin: cholesterol: the weight ratio of hydrogenated soya phosphatide is 3～4: 1: 2～3; Hydrogenated yolk lecithin preferably: cholesterol: the weight ratio of hydrogenated soya phosphatide is 3: 1: 2.
In an embodiment preferred of paroxetine hydrochloride lipidosome solid preparation of the present invention, the paroxetine hydrochloride liposome is processed by the supplementary material composition that comprises following weight proportion:
Based on the paroxetine hydrochloride of 1 weight portion, the amount of other pharmaceutic adjuvants is the 1-3.5 weight portion.
In this article; The meaning of used term " other pharmaceutic adjuvants " or " pharmaceutic adjuvant " and excipient equivalent in meaning; Be meant the pharmaceutic adjuvant except the paroxetine hydrochloride liposome that uses in order to prepare the paroxetine hydrochloride 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 paroxetine hydrochloride lipidosome solid preparation of the present invention; Said diluent is selected from one or more in starch, lactose, sorbitol, amylum pregelatinisatum, sorbitol, microcrystalline Cellulose, the pregelatinized Starch, is preferably pregelatinized Starch, sorbitol.
In an embodiment preferred of paroxetine hydrochloride 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, the polyvinylpolypyrrolidone, preferred low-substituted hydroxypropyl cellulose.
In an embodiment preferred of paroxetine hydrochloride 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 ethyl cellulose.
In an embodiment preferred of paroxetine hydrochloride 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 paroxetine hydrochloride lipidosome solid preparation of the present invention, said lubricant is selected from one or more in magnesium stearate, zinc stearate, Pulvis Talci, micropowder silica gel, Macrogol 4000, the stearic acid, is preferably Pulvis Talci.
Paroxetine hydrochloride lipidosome solid preparation provided by the invention is a tablet.
On the one hand, the present invention provides the method for preparing of above-mentioned paroxetine hydrochloride lipidosome solid preparation again, and this method may further comprise the steps:
(1) preparation of paroxetine hydrochloride liposome: paroxetine hydrochloride, hydrogenated yolk lecithin, cholesterol, hydrogenated soya phosphatide, polysorbate40 and PEG600 are prepared into the liposome powder together;
(2) preparation of paroxetine hydrochloride lipidosome solid preparation: liposome powder and other pharmaceutic adjuvants are mixed with the paroxetine hydrochloride lipidosome solid preparation.
Wherein, said pharmaceutic adjuvant is selected from diluent, disintegrating agent, binding agent, wetting agent, lubricant and combination thereof.
In the preferred implementation of the method for preparing of paroxetine hydrochloride liposome solid preparation, the preparation of step (1) paroxetine hydrochloride plastid comprises following substep:
(a) paroxetine hydrochloride, hydrogenated yolk lecithin, cholesterol, hydrogenated soya phosphatide, polysorbate40 and PEG600 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 46 ℃ 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 46 ℃ 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 paroxetine hydrochloride liposome powder.
In paroxetine hydrochloride 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, methanol, n-butyl alcohol, isopropyl alcohol, acetone, benzyl alcohol, the tert-butyl alcohol, the normal hexane, and preferred volume ratio is 3: 1 ethanol and an isopropyl alcohol mixed solvent.
In paroxetine hydrochloride 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 7.0 the phosphate buffered solution like the pharmacopeia record.
In an embodiment preferred of paroxetine hydrochloride lipidosome solid preparation method for preparing of the present invention, the preparation of step (2) paroxetine hydrochloride lipidosome solid preparation comprises following substep:
(e) paroxetine hydrochloride liposome powder and diluent, disintegrating agent and binding agent are mixed, the mix homogeneously that sieves adds wetting agent and prepares soft material, the preparation that sieves, drying;
(f) dried granule and mix lubricant is even, granulate sieves;
(g) tabletting makes the paroxetine hydrochloride lipidosome solid preparation.
The present invention becomes liposome through the active ingredient hydrochloric acid paroxetine with the combined preparation of the specified weight of hydrogenated yolk lecithin, cholesterol, hydrogenated soya phosphatide, 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 stripping property 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 paroxetine hydrochloride lipidosome solid preparation provided by the invention has improved product quality, and equipment is simple, processing ease, and method is simple, is suitable for industrialized great production.
With hereinafter, if 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 paroxetine hydrochloride liposome sheet
Used supplementary material is following:
Adopt following production technology to prepare paroxetine hydrochloride liposome sheet:
(1) accurately take by weighing 20g paroxetine hydrochloride, 30g hydrogenated yolk lecithin, 10g cholesterol, 20g hydrogenated soya phosphatide, 16g polysorbate40,24g PEG600, adding 400ml volume ratio is 3: 1 ethanol and an isopropyl alcohol mixed solvent, stirs and makes its dissolving;
(2) above-mentioned solution is placed eggplant-shape bottle, ethanol and isopropyl alcohol are removed in 46 ℃ of water-bath decompressions, on the bottle wall, form uniformly transparent film;
(3) in eggplant-shape bottle, adding the 400ml pH value is 7.0 phosphate buffered solution, continues to make the films swell hydration 46 ℃ 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 paroxetine hydrochloride liposome powder;
(5) paroxetine hydrochloride lipidosome solid powder and 12g sorbitol, 6g pregelatinized Starch, 4g low-substituted hydroxypropyl cellulose and 4g ethyl cellulose are mixed, the mix homogeneously that sieves adds 30% an amount of alcoholic solution and prepares soft material, the preparation that sieves, drying;
(6) with dried granule and 2g Pulvis Talci mix homogeneously, granulate sieves;
(7) tabletting makes 1000 paroxetine hydrochloride liposome sheets.
Embodiment 2 paroxetine hydrochloride liposome sheets
Used supplementary material is following:
Adopt following production technology to prepare paroxetine hydrochloride liposome sheet:
(1) accurately takes by weighing 20g paroxetine hydrochloride, 20g hydrogenated yolk lecithin, 6g cholesterol, 15g hydrogenated soya phosphatide, 14g polysorbate40,18g PEG600, add the 400ml volume ratio and be 3: 1 ethanol and isopropyl alcohol mixed solvent, stir and make its dissolving;
(2) above-mentioned solution is placed eggplant-shape bottle, ethanol and isopropyl alcohol are removed in 46 ℃ of water-bath decompressions, on the bottle wall, form uniformly transparent film;
(3) in eggplant-shape bottle, add 400ml pH value 7.0 salt buffer solutions, continue to make the films swell hydration 46 ℃ of water-bath normal pressure 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 paroxetine hydrochloride liposome powder;
(5) paroxetine hydrochloride lipidosome solid powder and 8g sorbitol, 6g pregelatinized Starch, 4g low-substituted hydroxypropyl cellulose and 4g ethyl cellulose are mixed, the mix homogeneously that sieves adds 30% an amount of alcoholic solution and prepares soft material, the preparation that sieves, drying;
(6) with dried granule and 2g Pulvis Talci mix homogeneously, granulate sieves;
(7) tabletting makes 1000 paroxetine hydrochloride liposome sheets.
Embodiment 3 paroxetine hydrochloride liposome sheets
Used supplementary material is following:
Adopt following production technology to prepare paroxetine hydrochloride liposome sheet:
(1) accurately take by weighing 20g paroxetine hydrochloride, 50g hydrogenated yolk lecithin, 16g cholesterol, 34g hydrogenated soya phosphatide, 18g polysorbate40,30g PEG600, adding 400ml volume ratio is 3: 1 ethanol and an isopropyl alcohol mixed solvent, stirs and makes its dissolving;
(2) above-mentioned solution is placed eggplant-shape bottle, ethanol and isopropyl alcohol are removed in 46 ℃ of water-bath decompressions, on the bottle wall, form uniformly transparent film;
(3) in eggplant-shape bottle, adding the 400ml pH value is 7.0 phosphate buffered solution, continues to make the films swell hydration 46 ℃ 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 paroxetine hydrochloride liposome powder;
(5) paroxetine hydrochloride lipidosome solid powder and 12g sorbitol, 6g pregelatinized Starch, 4g low-substituted hydroxypropyl cellulose and 4g ethyl cellulose are mixed, the mix homogeneously that sieves adds 30% an amount of alcoholic solution and prepares soft material, the preparation that sieves, drying;
(6) with dried granule and 2g Pulvis Talci mix homogeneously, granulate sieves;
(7) tabletting makes 1000 paroxetine hydrochloride liposome sheets.
Comparative Examples 1-4
Adopt with embodiment 1-3 in step (1)～(4) prepare the identical production technology of paroxetine hydrochloride liposome powder, the supplementary material composition in will the Comparative Examples 1-4 shown in following table 1 is processed paroxetine hydrochloride liposome powder respectively:
Raw materials used composition among the table 1 Comparative Examples 1-4
Wherein, "/" expression is not used.
The mensuration of Test Example 1 envelop rate
To carrying out quality investigation respectively with the paroxetine hydrochloride liposome powder of Comparative Examples 1-4 gained in the embodiment 1-3 step (4), mainly carry out liposome morphologic observation, particle size determination and liposome encapsulation and measure.
Wherein, liposome form and particle size determination adopt optical microscopy and the computing of statistica5.0 statistical software to observe about 2000 to average;
Entrapment efficiency determination is the conventional mensuration of liposome, adopts ultrafiltration to measure the envelop rate of paroxetine hydrochloride liposome.In brief, utilize ultrafiltration to isolate free drug; Utilize methanol to destroy liposome, carry out assay with HPLC method and standard control then, calculate entrapment efficiency according to the envelop rate formula to extract medicine.
The result is 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 paroxetine hydrochloride liposome of the present invention will exceed a lot.
Can know that through comparing embodiment 1-3 and Comparative Examples 1-4 liposome of the present invention has higher envelop rate.The envelop rate of paroxetine hydrochloride liposome is relevant with the composition that is used to form liposome.Especially, when the composition beyond the used composition of use the present invention, the envelop rate of gained paroxetine hydrochloride liposome is starkly lower than the present invention.
Can know that through comparing embodiment 1-3 and Comparative Examples 1-4 (especially 3) envelop rate of paroxetine hydrochloride liposome is not only relevant with the composition that is used to form liposome, also directly related with the consumption of each composition.When the composition consumption was outside the composition amount ranges that the present invention limits, the envelop rate of gained paroxetine hydrochloride liposome was starkly lower than the present invention.
Percolation ratio is by formula Q
Ooze%=(W
Bag-W
Storage)/W
Bag* 100% calculates percolation ratio.The sample percolation ratio of inventive embodiments 1-3 preparation is very low, and less than 3% or almost there is not the seepage phenomenon, and the sample permeability of Comparative Examples 1-4 preparation increases gradually, and percolation ratio can reach 30%.
The size and the particle size distribution of Test Example 2 liposome particle diameters
In order to understand paroxetine hydrochloride liposome particle size parameters and particle size distribution accurately; Be taken at an amount of liposome powder of gained in the step (4) among embodiment 1-3 and the Comparative Examples 1-4; Directly with laser particle size analyzer (Easysizer20; America and Europe's gram company) observes its outer light; 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 1-4 among the embodiment of the invention 1-3, and the size homogeneous, outward appearance is better.
Can know that through comparing embodiment and Comparative Examples liposome of the present invention has littler mean diameter, particle size distribution is more even, and outward appearance is better.This shows that the particle diameter of paroxetine hydrochloride 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 character such as mean diameter, particle size distribution and outward appearance of gained paroxetine hydrochloride liposome obviously are inferior to the present invention.
Can know that through comparing embodiment 1-3 and Comparative Examples 1-4 liposome of the present invention has littler mean diameter, particle size distribution is more even, and outward appearance is better.This shows that the particle diameter of paroxetine hydrochloride liposome is not only relevant with the composition that is used to form liposome, and is also directly related with the consumption of each composition.When the composition consumption was outside the composition amount ranges that the present invention limits, the character such as mean diameter, particle size distribution and outward appearance of gained paroxetine hydrochloride liposome obviously were 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; 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 paroxetine hydrochloride 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 paroxetine hydrochloride sheet (Sino-America Tianjin Shike Pharmaceutical Co., Ltd.'s lot number 20100701) 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 paroxetine hydrochloride sheet dissolution of listing is low, content reduces obviously when quickening June, and related substance raises; And the sample dissolution of preparation is high in the embodiment of the invention 1 and 3, quickens that content and related substance all do not have significant change after 6 months.Proved absolutely the present invention at the superiority that improves aspect stability and the dissolution, obtained can't rational expectation beyond thought effect.
Test Example 4 release in vitro researchs
Precision takes by weighing the paroxetine hydrochloride sheet (Sino-America Tianjin Shike Pharmaceutical Co., Ltd.'s lot number 20100701) of listing and each 1g of sample (amount with paroxetine hydrochloride is as the criterion) of embodiment 1-3 is dissolved in the 10ml water; Accurate each 2ml of suspension that draws places bag filter to tighten; Be fixed on the stirring paddle of digestion instrument; Release medium is phosphate buffered solution (containing 0.25% the polysorbas20) 100ml of pH 6.8; Bath temperature is 37 ℃; 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 correlated paroxetine hydrochloride sheet of curve 1 expression listing, 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 paroxetine hydrochloride listing medicine rate of release is very fast, and the release of gained paroxetine hydrochloride lipidosome solid preparation is slow among the embodiment of the invention 1-3, has reached the effect of slow release.
Industrial applicibility
Result by the foregoing description and Test Example can know; Paroxetine hydrochloride lipidosome solid preparation of the present invention has good surface appearance; Granule is little, and particle diameter is even, and envelop rate is high; 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 describe the present invention; 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; We carry out multiple modification, improvement and replacement to technical scheme of the present invention and embodiment thereof, and these all are in protection scope of the present invention.
The list of references of mentioning in the application of quoting, at this in full for reference only.
Claims (10)
1. paroxetine hydrochloride liposome, it is processed by the supplementary material composition that comprises following weight proportion:
Condition is: hydrogenated yolk lecithin: cholesterol: the weight ratio of hydrogenated soya phosphatide is 3～4: 1: 2～3; Hydrogenated yolk lecithin preferably: cholesterol: the weight ratio of hydrogenated soya phosphatide is 3: 1: 2.
2. paroxetine hydrochloride liposome according to claim 1, it is preferably the supplementary material composition that comprises following weight proportion and processes:
3. the method for preparing of the arbitrary said paroxetine hydrochloride liposome of claim 1-2, this method may further comprise the steps:
(a) paroxetine hydrochloride, hydrogenated yolk lecithin, cholesterol, hydrogenated soya phosphatide, polysorbate40 and PEG600 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 46 ℃ 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 46 ℃ 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 multigelations three times, spray drying makes paroxetine hydrochloride liposome powder.
4. method according to claim 3; Wherein, Organic solvent described in the step (a) is selected from one or more in ethanol, chloroform, dichloromethane, methanol, n-butyl alcohol, isopropyl alcohol, acetone, benzyl alcohol, the tert-butyl alcohol, the normal hexane, and preferred volume ratio is 3: 1 the ethanol and the mixed solvent of isopropyl alcohol;
Buffer salt solution described in the step (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 7.0 phosphate buffered solution.
5. paroxetine hydrochloride lipidosome solid preparation, it is processed by the arbitrary described paroxetine hydrochloride liposome of claim 1-2 and other pharmaceutic adjuvants.
6. paroxetine hydrochloride lipidosome solid preparation according to claim 5, wherein based on the paroxetine hydrochloride of 1 weight portion, the amount of other pharmaceutic adjuvants is 1-3.5 part.
7. according to the arbitrary described lipidosome solid preparation of claim 5-6, it is a tablet.
8. method for preparing according to the arbitrary said paroxetine hydrochloride lipidosome solid preparation of claim 5-6, this method may further comprise the steps:
(1) preparation of paroxetine hydrochloride liposome: paroxetine hydrochloride, hydrogenated yolk lecithin, cholesterol, hydrogenated soya phosphatide, polysorbate40 and PEG600 are prepared into the liposome powder together;
(2) preparation of paroxetine hydrochloride lipidosome solid preparation: liposome powder and other pharmaceutic adjuvants are mixed with the paroxetine hydrochloride lipidosome solid preparation.
9. method according to claim 8, wherein the preparation of step (1) paroxetine hydrochloride liposome comprises following substep:
(a) paroxetine hydrochloride, hydrogenated yolk lecithin, cholesterol, hydrogenated soya phosphatide, polysorbate40 and PEG600 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 46 ℃ 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 46 ℃ 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 multigelations three times, spray drying makes paroxetine hydrochloride liposome powder;
Wherein, Organic solvent described in the substep (a) is selected from one or more in ethanol, chloroform, dichloromethane, methanol, n-butyl alcohol, isopropyl alcohol, acetone, benzyl alcohol, the tert-butyl alcohol, the normal hexane, and preferred volume ratio is 3: 1 ethanol and an isopropyl alcohol mixed solvent;
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 7.0 phosphate buffered solution.
10. method according to claim 8, wherein, the preparation of step (2) paroxetine hydrochloride liposome solid preparation comprises following substep:
(e) paroxetine hydrochloride 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, and drying must be done granule.
(g) tabletting makes the paroxetine hydrochloride lipidosome solid preparation.
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