CN102579350B - Pidotimod liposome solid preparation - Google Patents
Pidotimod liposome solid preparation Download PDFInfo
- Publication number
- CN102579350B CN102579350B CN 201210053024 CN201210053024A CN102579350B CN 102579350 B CN102579350 B CN 102579350B CN 201210053024 CN201210053024 CN 201210053024 CN 201210053024 A CN201210053024 A CN 201210053024A CN 102579350 B CN102579350 B CN 102579350B
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- CN
- China
- Prior art keywords
- liposome
- ibuprofen
- preparation
- pidotimod
- solid preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Abstract
The invention discloses a pidotimod liposome solid preparation and a preparation method thereof. The pidotimod liposome with excellent quality is prepared by selecting pidotimod, phosphatidylinositol, cholesterol, stigmasterol and cremophor HEL 40 in specific weight ratios and then the pidotimod liposome is prepared into the solid preparation by a common preparation method. The liposome solid preparation and preparation method provided by the invention have the following beneficial effects: the liposome solid preparation has high encapsulation efficiency and uniform grain size; the retention time of medicaments in blood circulation is long; and the preparation method is simple and practical, is beneficial to improvement of the product quality and reduction of the toxic or side effect and is suitable for industrial large-scale production.
Description
Technical field
The present invention relates to a kind of lipidosome solid preparation, be specifically related to a kind of Pidotimod liposome solid preparation, belong to medical technical field.
Background technology
(S)-ibuprofen (Pidotimod) is is at first researched and developed successfully by Austrian Gebro-Broscheh Gmb H company, and chemical name was (S)-(+)-2-(4-isobutylphenyl) propanoic acid, molecular formula C through the approval listing in 1994
13H
18O
2, molecular weight 206.28, structural formula is:
Ibuprofen belongs to propionic non-steroid antiphlogistic, tool analgesia, antiinflammatory, refrigeration function, its mechanism is by the epoxy enzymeinhibition being reduced the synthetic of prostaglandin, alleviate thus congested, the swelling of the tissue that causes because of prostaglandin, reduce the sensitivity of the peripheral nerve pain sensation, it plays refrigeration function by the hypothalamus center of body temperature regulation.Although ibuprofen is NSAID (non-steroidal anti-inflammatory drug) at present commonly used, because oral dose is large, the reasons such as the poor and GI irritation of mouthfeel have affected its extensive use.Many clinical adverse have appearred in ibuprofen in recent years, send out and should, anaphylactic shock, lower limbs edema, feel sick vomiting, dyspepsia etc. such as allergy.The clinical application DL ibuprofen of also having taked replaces ibuprofen, as antiinflammatory, analgesic, existing 30 years of its clinical practice, the DL ibuprofen is comprised of left-handed ibuprofen and (S)-ibuprofen, the left-handed ibuprofen of 50%-60% in body " metabolic counter-rotating " becomes (S)-ibuprofen competence exertion therapeutical effect, improve therapeutical effect, reduce the dosage of medicine.But the left-handed ibuprofen in the DL ibuprofen has also produced other when being converted to (S)-ibuprofen covert isomer, cause occurring some side reactions: gastrointestinal toxicity, water-sodium retention, stomach perfusion reduce and anaphylaxis, and incidence rate is 15%～30%.Research in recent years finds that the activity of (S)-ibuprofen is 160 times of its levo form, is 16 times of raceme.Therefore, (S)-ibuprofen has higher activity and curative effect, and smaller dose can reach therapeutical effect, can effectively reduce toxic and side effects.
CN101829064A discloses a kind of (s)-ibuprofen granules preparation and preparation method thereof that comprises, it mixes the rear abundant mixing that sieves with active component (S)-ibuprofen and diluent, cosolvent, sweeting agent, binding agent, granulate, after the high temperature drying, granulate namely gets (s)-ibuprofen granules.But the granule practicality that this method conventional method makes is restricted, and retention cycle is shorter, and bioavailability is lower.CN102160855A discloses a kind of Dex-ibuprofen sustained release tablets and preparation method and application, has improved the formula components ratio, but still or general pharmaceutic adjuvant and conventional traditional film-making technique of usefulness.Although it is easy that this slow releasing tablet is taken, but its rate of release and sustained release ability remain further to be improved, and the low shortcoming of solid preparation bioavailability of traditional method preparation still exists.CN101077339A discloses a kind of Dexibuprofen effervescent tablet and its preparation method and application, although it is easy that this disintegrating tablet is taken, but its rate of release and sustained release ability remain further to be improved, and contain in its sheet the alkaline auxiliary solvent and acid, alkaline disintegrating agent, bad person is inapplicable to gastrointestinal tract, and its bioavailability also has much room for improvement.CN101077343B discloses a kind of (s)-ibuprofen granules preparation and preparation method thereof, but the bioavailability of conventional particles agent is low.
The (S)-ibuprofen class pharmaceutical dosage form of above-mentioned present listing has tablet, capsule, suppository and oral administration mixed suspension, although these dosage forms have been screened specific adjuvant and have been prepared, having must advantage, but the long-time stability of medicine are undesirable, be unfavorable for long-term storage, drug releasing rate and drug release process can not be controlled, thereby bring hidden danger can for clinical use.
Liposome refers to drug encapsulation made spherical targeted drug carrier formulation of superminiature in the middle of the thin film that the lipoids bimolecular forms is belonged to a kind of novel form of targeting drug delivery system.Liposome has plurality of advantages as pharmaceutical carrier: can seal fat-soluble medicine such as liposome, can seal water soluble drug again; Alleviate allergy and immunoreation; Delay to discharge, reduce elimination speed in the body; Can effectively protect and be wrapped medicine, improve bioavailability; Change medicine distribution in vivo, and can the targeting release, the toxic and side effects of medicine can be reduced; Be fit to multipath administration etc.Liposome Main Function mechanism is drug powder or solution are wrapped in the aqueous phase that the liposome bilayer lipid membrane seals or embed in the liposome bilayer lipid membrane, this microgranule has the class cellularity, enter the interior principal agent of human body is activated body by reticuloendothelial system phagocytic autoimmune function, and the interior distribution of the body that changes encapsulated medicine, drug main will be put aside in the histoorgans such as liver, spleen, lung and bone marrow, thereby improve the therapeutic index of medicine, reduce the toxicity of therapeutic dose and the reduction medicine of medicine.
CN101732255A discloses a kind of flurbiprofen liposome, take by weighing by weight first 1～10 part in cholesterol, 5～40 parts of Ovum Gallus domesticus Flavus lecithins, 1～10 part of 2～50 parts of flurbiprofens and vitamin C, make their dissolvings with chloroform/methanol again, and mix homogeneously obtains mixed solution, then above-mentioned mixed solution is placed Rotary Evaporators, chloroform and methanol are removed in distilling under reduced pressure, making lipid film, then is that 6～8 phosphate buffer joins in the lipid film with pH, is rotating 1～4h on the Rotary Evaporators in 20～60 ℃ of temperature are bathed, behind the last ultrasonic 5～30min of water-bath, the filter membrane of crossing 22～45 μ m makes flurbiprofen liposome.
CN102198132A discloses a kind of ketoprofen omeprazole Liposomal formulation, main by the ketoprofen 5-10 part based on weighing scale, 1 part of omeprazole, hydrogenated yolk lecithin 10-80 part, cholesterol 3-40 part, the liposome that 5-10 part Tween 80 is made, and further disclose by ketoprofen omeprazole Liposomal formulation and add a kind of ketoprofen omeprazole pharmaceutical composition solid preparation that other pharmaceutically commonly used excipient are made.EP2301525A discloses a kind of ibuprofen liposome localized liquid preparation, is made by ibuprofen, lecithin or phosphatidylcholine, sodium cholate and ethanol.
Prior art does not disclose the lipidosome solid preparation of (S)-ibuprofen, and the prescription of above-mentioned liposome also is not suitable for because therefore the solid preparation of preparation (S)-ibuprofen liposome needs a kind of (S)-ibuprofen lipidosome solid dosage form of exploitation to overcome the defective of prior art.
Summary of the invention
In order to improve the stability of (S)-ibuprofen, improve bioavailability, strengthen its targeting, the inventor studies Pidotimod liposome solid preparation.Find that by a large amount of experiments the lipidosome solid preparation that adopts particular excipient and (S)-ibuprofen to make has effectively overcome the problem of principal agent poor stability, improved simultaneously the dissolution of medicine, increased medicine retention time in vivo.
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 such as 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 pharmaceutical properties that will seal, therefore, selecting which type of composition to form the (S)-ibuprofen liposome with better quality is the problem that needs to be resolved hurrily.
The inventor is through with keen determination research discovery, by (S)-ibuprofen, phosphatidylinositols, cholesterol, stigmasterol and the polyoxyl 40 hydrogenated castor oil of selecting the specified weight proportioning, can form the (S)-ibuprofen liposome of excellent quality, again the (S)-ibuprofen liposome is made solid preparation with general formulation method, thereby finish the present invention.
The objective of the invention is to be to provide a kind of (S)-ibuprofen liposome, it is made by the composition that comprises following weight proportion:
Condition is: weight sum and the weight ratio between the phosphatidylinositols of cholesterol and stigmasterol are 1: 1-1: 3.
Another object of the present invention provides the preparation method of above-mentioned (S)-ibuprofen liposome, and the method may further comprise the steps:
(a) (S)-ibuprofen, phosphatidylinositols, cholesterol, stigmasterol and polyoxyl 40 hydrogenated castor oil are dissolved in the organic solvent, mix homogeneously, organic solvent is removed in decompression on rotary film evaporator, obtains lipid membrane;
(b) under nitrogen protection, in bottle, add buffer solution, jolting was stirred 30 minutes, rotating speed was 400-700r/min, makes the complete aquation of immobilized artificial membrane, with the homogeneous emulsifying 10-15 of tissue mashing machine's high speed minute, rotating speed 5000r/min with 0.45 μ m filtering with microporous membrane, makes liposome turbid liquor;
(c) with above-mentioned liposome turbid liquor spray drying, make (S)-ibuprofen liposome powder.
A further object of the present invention provides a kind of Pidotimod liposome solid preparation, and it is made by (S)-ibuprofen liposome and other pharmaceutic adjuvants, and wherein said (S)-ibuprofen liposome is made by the composition that comprises following weight proportion:
Condition is: weight sum and the weight ratio between the phosphatidylinositols of cholesterol and stigmasterol are 1: 1-1: 3;
Based on the (S)-ibuprofen of 1 weight portion, the amount of other pharmaceutic adjuvants is 0.5-5 part.
Described Pidotimod liposome solid preparation is oral formulations, comprises the Tablet and Capsula agent.
A further object of the present invention provides the preparation method of above-mentioned Pidotimod liposome solid preparation, and the method may further comprise the steps:
(1) preparation of (S)-ibuprofen liposome: (S)-ibuprofen and phosphatidylinositols, cholesterol, stigmasterol and polyoxyl 40 hydrogenated castor oil are mixed with the liposome powder;
(2) preparation of Pidotimod liposome solid preparation: the (S)-ibuprofen liposome is mixed with other pharmaceutic adjuvants, the preparation Pidotimod liposome solid preparation, wherein said other pharmaceutic adjuvant comprises diluent: lactose 0.5-1 part and microcrystalline Cellulose 0.3-1 part, disintegrating agent: polyvinylpolypyrrolidone 0.1-0.8 part, binding agent: xanthan gum 0.05-0.5 part, lubricant: or zinc stearate 0.02-0.05 part; And combination.
Wherein, the preparation of step (1) (S)-ibuprofen liposome comprises following substep:
(a) (S)-ibuprofen, phosphatidylinositols, cholesterol, stigmasterol and polyoxyl 40 hydrogenated castor oil are dissolved in the organic solvent, mix homogeneously, organic solvent is removed in decompression on rotary film evaporator, obtains lipid membrane;
(b) under nitrogen protection, in bottle, add buffer solution, jolting was stirred 30 minutes, rotating speed was 400-700r/min, makes the complete aquation of immobilized artificial membrane, with the homogeneous emulsifying 10-15 of tissue mashing machine's high speed minute, rotating speed 5000r/min with 0.45 μ m filtering with microporous membrane, makes liposome turbid liquor;
(c) with above-mentioned liposome turbid liquor spray drying, make (S)-ibuprofen liposome powder;
The preparation of step (2) Pidotimod liposome solid preparation comprises following substep:
(d) (S)-ibuprofen liposome powder and diluent, disintegrating agent are mixed, cross 80 mesh sieve mix homogeneously, add binder solution and prepare soft material, cross 20 mesh sieves and granulate drying;
(e) dried granule and mix lubricant is even, cross 20 mesh sieve granulate;
(f) tabletting or filled capsules make Pidotimod liposome solid preparation.
Pidotimod liposome solid preparation provided by the invention has improved the bioavailability of (S)-ibuprofen, improve the quality of formulation products, reduced toxic and side effects, increased the concentration in the target organ of medicine, the time that medicine distributes in the body circulation is longer, and curative effect obviously improves.
Description of drawings
Fig. 1 is the time release profiles of Pidotimod liposome solid preparation, the time release of prepared Pidotimod liposome solid preparation sample among expression embodiment 1-3 and the Comparative Examples 1-3, wherein: curve 1 is the (S)-ibuprofen release profiles of prepared sample among the embodiment 1; Curve 2 is the (S)-ibuprofen release profiles of prepared sample among the embodiment 2; Curve 3 is the (S)-ibuprofen release profiles of prepared sample among the embodiment 3; Curve 4 is the (S)-ibuprofen release profiles of prepared sample in the Comparative Examples 1; Curve 5 is the (S)-ibuprofen release profiles of prepared sample in the Comparative Examples 2; Curve 6 is the (S)-ibuprofen release profiles of prepared sample in the Comparative Examples 3.
The specific embodiment
Below further specify by 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 Pidotimod liposome solid preparation, can good compatible with (S)-ibuprofen it well be sealed and non-leakage filmogen thereby importantly seek, in order to form colory (S)-ibuprofen liposome, and seek the pharmaceutic adjuvant that can form with the (S)-ibuprofen liposome solid preparation.
To achieve these goals, large quantity research and realization that the inventor carries out, (S)-ibuprofen, phosphatidylinositols, cholesterol, stigmasterol and the polyoxyl 40 hydrogenated castor oil of discovery specified weight proportioning can be made the (S)-ibuprofen liposome, wherein, envelop rate as the (S)-ibuprofen of active constituents of medicine is high, the liposome particle diameter is little and be evenly distributed, the retention time significant prolongation of (S)-ibuprofen in the solid preparation in the body circulation, targeting improves, bioavailability obviously improves, and curative effect obviously improves.
On the one hand, the invention provides a kind of (S)-ibuprofen liposome, it is made by the composition that comprises following weight proportion:
Condition is: weight sum and the weight ratio between the phosphatidylinositols of cholesterol and stigmasterol are 1: 1-1: 3.
Preferably, described (S)-ibuprofen liposome is made by the composition that comprises following weight proportion:
Condition is: weight sum and the weight ratio between the phosphatidylinositols of cholesterol and stigmasterol are 1: 1-1: 2.
Most preferably, described (S)-ibuprofen liposome is made by the composition that comprises following weight proportion:
Condition is: weight sum and the weight ratio between the phosphatidylinositols of cholesterol and stigmasterol are 1: 1-1: 1.5.
As the phospholipid that is used to form liposome, can use natural phospholipid and synthetic phospholipid.Natural phospholipid comprises PHOSPHATIDYL ETHANOLAMINE, phosphatidyl glycerol, Phosphatidylserine, phosphatidylinositols, Ovum Gallus domesticus Flavus lecithin, hydrogenated yolk lecithin, EPG, egg yolk lecithin acyl serine, PI, soybean lecithin, hydrogenated soy phosphatidyl choline, hydrolecithin, EPG, lecithin acyl serine and lecithin acyl inositol etc.Synthetic phospholipid is for example PEG-DSPE 2000 (DSPE-mPEG of DOPC, DSPC, dipalmitoyl phosphatidyl choline, DMPC, DLPC, DOPG, DSPG, DPPG, GLYCEROL,DIMYRISTOYL PHOSPHATIDYL, PE and polyglycol derivatization phospholipid
2000); Two soft ester acyl gallbladder phospholipid-Macrogol 2000 (DPPG-mPEG
2000); HSPC-Macrogol 2000 (HSPC-mPEG
2000); DOPC-Macrogol 2000 (DOPC-mPEG
2000Deng.
The inventor finds that through research phosphatidylinositols is particularly suitable for sealing (S)-ibuprofen as basic immobilized artificial membrane material, thereby forms the liposome of high-quality.Phosphatidylinositols is a kind of natural phospholipid, is easy to form stable liposome membrane.When using other above-mentioned phospholipid, be difficult to form colory liposome, the character such as the envelop rate of liposome, stability and percolation ratio are poor.
In (S)-ibuprofen liposome of the present invention, for the (S)-ibuprofen of 1 weight portion, the consumption of phosphatidylinositols is the 1-20 weight portion.If the consumption of phosphatidylinositols is lower than 1 weight portion, it is not encapsulated to have a large amount of free (S)-ibuprofens, and the drug loading of liposome is low; Otherwise if the consumption of the consumption of phosphatidylinositols is higher than 20 weight portions, then the envelop rate as the (S)-ibuprofen of active constituents of medicine descends.
In (S)-ibuprofen liposome of the present invention, the collaborative membrane stability that is used for regulating liposome of cholesterol and stigmasterol.
Cholesterol is a kind of amphiphilic, combines with phosphatidylinositols, stops it to be condensed into crystal structure.Cholesterol mixes in the phosphatidylinositols duplicature, 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 the liposome bi-layer membrane solidify, thereby reduces the generation of free radical, reduces oxidation level, and liposome stability is significantly strengthened.
Stigmasterol (Stigmasterol) is to extract a plant sterols that forms from the concise product of soybean oil, and is without any side effects, is cholesterol reducing, prevention and cure of cardiovascular disease, anticancer desirable material.As a kind of natural product, the stigmasterol source is abundant, low price.With cholesterol seemingly, stigmasterol also can be regulated the stability of phosphatidylinositols film, and its regulating action effect to stability is better than cholesterol.
The inventor finds through research, when weight sum and the phosphatidylinositols weight ratio of cholesterol and stigmasterol is 1: 1-1: in the time of 3, can form stable (S)-ibuprofen liposome.When the weight sum of cholesterol and stigmasterol and phosphatidylinositols weight ratio were higher than 1: 1, membrane stability reduced, and (S)-ibuprofen is easy to seepage; When the weight sum of cholesterol and stigmasterol and phosphatidylinositols weight ratio were lower than 1: 3, (S)-ibuprofen liposome membrane flowability was too high, and the (S)-ibuprofen that is wrapped in the liposome is easy to discharge.In addition, research finds, when weight sum and the phosphatidylinositols weight ratio of cholesterol and stigmasterol is 1: 1-1: in the time of 3, formed liposome toxicity is low.
Studies show that the stability of liposome and bioavailability have close corresponding relation.Stability is higher, and bioavailability is higher.Therefore, the stability of (S)-ibuprofen liposome of the present invention is high, is to cause one of high factor of drug bioavailability.
In addition, the inventor studies discovery, in (S)-ibuprofen liposome of the present invention, for the (S)-ibuprofen of 1 weight portion, the consumption of phosphatidylinositols is the 1-20 weight portion, and cholesterol is the 0.5-10 weight portion, and stigmasterol is the 0.5-5 weight portion, and the weight sum of cholesterol and stigmasterol and phosphatidylinositols weight ratio are 1: 1-1: 3 o'clock, the envelop rate of formed (S)-ibuprofen liposome was high.
In (S)-ibuprofen liposome of the present invention, further improve the stability of liposome membrane with polyoxyl 40 hydrogenated castor oil.Polyoxyl 40 hydrogenated castor oil is a kind of non-ionic surface active agent, when being used for the phosphatidylinositols duplicature, can modify and improve the character of membrane material, improve the chemical energy between this duplicature, thereby improve the chemical stability of liposome in waterborne liquid, with the dissolubility and the envelop rate that improve medicine, and then the stability of raising (S)-ibuprofen liposome.
In (S)-ibuprofen liposome of the present invention, for the (S)-ibuprofen of 1 weight portion, the consumption of polyoxyl 40 hydrogenated castor oil is the 1-10 weight portion.If the consumption of polyoxyl 40 hydrogenated castor oil is lower than 1 weight portion, then cause the stability improvement of (S)-ibuprofen liposome inadequate owing to its consumption is excessively low, otherwise, if the consumption of polyoxyl 40 hydrogenated castor oil is higher than 10 weight portions, it is too high and cause liposome membrane to be easy to reveal then to be used for its consumption.
Research is found, when the (S)-ibuprofen that uses above-mentioned specified quantitative, phosphatidylinositols, cholesterol, stigmasterol and polyoxyl 40 hydrogenated castor oil, can obtain colory (S)-ibuprofen liposome, its envelop rate and stability are all very high, toxicity is low, rate of release is low, and targeting is high, and bioavailability is high.Bound by theory not it will be appreciated by those skilled in the art that, the present invention may be that phosphatidylinositols, cholesterol, stigmasterol and polyoxyl 40 hydrogenated castor oil are to the synergistic result of (S)-ibuprofen.
On the other hand, the invention provides the preparation method of (S)-ibuprofen liposome, the method may further comprise the steps:
(a) (S)-ibuprofen, phosphatidylinositols, cholesterol, stigmasterol and polyoxyl 40 hydrogenated castor oil are dissolved in the organic solvent, mix homogeneously, organic solvent is removed in decompression on rotary film evaporator, obtains lipid membrane;
(b) under nitrogen protection, in bottle, add buffer solution, jolting was stirred 30 minutes, rotating speed was 400-700r/min, makes the complete aquation of immobilized artificial membrane, with the homogeneous emulsifying 10-15 of tissue mashing machine's high speed minute, rotating speed 5000r/min with 0.45 μ m filtering with microporous membrane, makes liposome turbid liquor;
(c) with above-mentioned liposome turbid liquor spray drying, make (S)-ibuprofen liposome powder.
In a preferred embodiment of (S)-ibuprofen method for preparing lipidosome of the present invention, organic solvent is selected from one or more in ethanol, methanol, the tert-butyl alcohol, n-butyl alcohol, isopropyl alcohol, acetone, acetonitrile, benzyl alcohol, normal hexane and the dichloromethane described in the step (a), and preferred volume ratio is 3: 1 ethanol and the mixed solvent of acetone.
In a preferred embodiment of (S)-ibuprofen method for preparing lipidosome of the present invention, buffer solution described in the step (b) is selected from a kind of in phosphate buffer, citrate buffer, acetate buffer and the carbonate buffer solution, preferred pH value is 6.5 phosphate buffered solution, pH value is that 6.5 phosphate buffered solution is known in the art, and for example the pharmacopeia appendix is put down in writing.
By said method, can prepare the little and uniform (S)-ibuprofen liposome of particle size distribution of granule, its envelop rate is high, and stability is high, is difficult for leaking, and bioavailability is high.
Research finds, the size of liposome is affect that liposome distributes in vivo and the principal element of the time of staying, and the particle diameter of liposome is less, and the interior time of staying of body is longer.(S)-ibuprofen liposome particles by 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.
Liposome of the present invention has reached following requirement: (1) liposome form rounding and not assembling, and effectively controlled particle size range; (2) liposome stability is high, can place for a long time; (3) liposome has higher envelop rate and drug loading.
On the one hand, the invention provides Pidotimod liposome solid preparation again, it is made by (S)-ibuprofen liposome and other pharmaceutic adjuvants, and wherein said (S)-ibuprofen liposome is made by the composition that comprises following weight proportion:
Condition is: weight sum and the weight ratio between the phosphatidylinositols of cholesterol and stigmasterol are 1: 1-1: 3.
In a preferred embodiment of Pidotimod liposome solid preparation of the present invention, the (S)-ibuprofen liposome is made by the composition that comprises following weight proportion:
Condition is: weight sum and the weight ratio between the phosphatidylinositols of cholesterol and stigmasterol are 1: 1-1: 2.
In a preferred embodiment, the (S)-ibuprofen liposome is made by the composition that comprises following weight proportion:
Condition is: weight sum and the weight ratio between the phosphatidylinositols of cholesterol and stigmasterol are 1: 1-1: 1.5.
In a preferred embodiment of Pidotimod liposome solid preparation of the present invention, based on the (S)-ibuprofen 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, refer to the medicinal material except the (S)-ibuprofen liposome that uses in order to prepare Pidotimod liposome solid preparation comprise diluent: lactose 0.5-1 part and microcrystalline Cellulose 0.3-1 part, disintegrating agent: polyvinylpolypyrrolidone 0.1-0.8 part, binding agent: xanthan gum 0.05-0.5 part or lubricant: zinc stearate 0.02-0.05 part; And combination.
In this article, used term " amounts of other pharmaceutic adjuvants " refers to 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 a preferred embodiment of Pidotimod liposome solid preparation of the present invention, diluent is selected from one or more in starch, pregelatinated lactose, lactose, sorbitol, microcrystalline Cellulose, the dextrin, is preferably lactose and microcrystalline Cellulose.
In a preferred embodiment of Pidotimod liposome solid preparation of the present invention, disintegrating agent is selected from one or more of low-substituted hydroxypropyl cellulose, carboxymethylstach sodium, cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone, preferred polyvinylpolypyrrolidone.
In a preferred embodiment of Pidotimod liposome solid preparation of the present invention, binding agent is selected from a kind of in PVP K30, lactose slurry, hypromellose, sodium carboxymethyl cellulose, ethyl cellulose, arabic gum, the xanthan gum, is preferably xanthan gum.In a preferred embodiment of Pidotimod liposome solid preparation of the present invention, adhesive solvent is selected from the alcoholic solution of 20-70%, preferred 50% alcoholic solution.
In a preferred embodiment of Pidotimod liposome solid preparation of the present invention, lubricant is selected from one or more in magnesium stearate, zinc stearate, Pulvis Talci, micropowder silica gel, Macrogol 4000, the stearic acid, is preferably zinc stearate.
Pidotimod liposome solid preparation provided by the invention is oral formulations, comprises the Tablet and Capsula agent.Its specification is that per unit preparation (S)-ibuprofen is 200mg, 150mg.
Again on the one hand, the invention provides the preparation method of above-mentioned Pidotimod liposome solid preparation, the method may further comprise the steps:
(1) preparation of (S)-ibuprofen liposome: (S)-ibuprofen and phosphatidylinositols, cholesterol, stigmasterol and polyoxyl 40 hydrogenated castor oil are mixed with the liposome powder;
(2) preparation of Pidotimod liposome solid preparation: the (S)-ibuprofen liposome is mixed with other pharmaceutic adjuvants, the preparation Pidotimod liposome solid preparation, wherein said other pharmaceutic adjuvant is selected from and comprises diluent: lactose 0.5-1 part and microcrystalline Cellulose 0.3-1 part, disintegrating agent: polyvinylpolypyrrolidone 0.1-0.8 part, binding agent: xanthan gum 0.05-0.5 part or lubricant: zinc stearate 0.02-0.05 part; And combination.
Wherein, the preparation of step (1) (S)-ibuprofen liposome comprises following substep:
(a) (S)-ibuprofen, phosphatidylinositols, cholesterol, stigmasterol and polyoxyl 40 hydrogenated castor oil are dissolved in the organic solvent, mix homogeneously, organic solvent is removed in decompression on rotary film evaporator, obtains lipid membrane;
(b) under nitrogen protection, in bottle, add buffer solution, jolting was stirred 30 minutes, rotating speed was 400-700r/min, makes the complete aquation of immobilized artificial membrane, with the homogeneous emulsifying 10-15 of tissue mashing machine's high speed minute, rotating speed 5000r/min with 0.45 μ m filtering with microporous membrane, makes liposome turbid liquor;
(c) with above-mentioned liposome turbid liquor spray drying, make (S)-ibuprofen liposome powder;
The preparation of step (2) Pidotimod liposome solid preparation comprises following substep:
(d) (S)-ibuprofen liposome powder and diluent, disintegrating agent are mixed, cross 80 mesh sieve mix homogeneously, add binder solution and prepare soft material, cross 20 mesh sieves and granulate drying;
(e) dried granule and mix lubricant is even, cross 20 mesh sieve granulate;
(f) tabletting or filled capsules make Pidotimod liposome solid preparation.
In a preferred embodiment of Pidotimod liposome solid preparation preparation method of the present invention, organic solvent is selected from one or more in ethanol, methanol, the tert-butyl alcohol, n-butyl alcohol, isopropyl alcohol, acetone, acetonitrile, benzyl alcohol, normal hexane and the dichloromethane described in the substep (a), and preferred volume ratio is 3: 1 ethanol and the mixed solvent of acetone.
In a preferred embodiment of (S)-ibuprofen method for preparing lipidosome of the present invention, buffer solution described in the substep (b) is selected from a kind of in phosphate buffer and citrate buffer, the acetate buffer, and preferred pH value is 6.5 phosphate buffered solution.
In the method for the invention, can also sterilize to liposome 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, such as heat sterilization, filtration sterilization, radiation sterilization or sterile working etc.
The Pidotimod liposome solid preparation that the present invention makes has improved the quality of formulation products, has reduced toxic and side effects, has increased the retention time of medicine in the body circulation, has improved the bioavailability of medicine, and curative effect obviously improves; And preparation method is simple, is suitable for industrialized great production.
In this article, if not especially explanation, content or consumption are all by weight.
Embodiment
Below by 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.
The preparation of embodiment 1 (S)-ibuprofen liposome sheet
Used supplementary material is as follows:
Adopt following production technology to prepare (S)-ibuprofen liposome sheet:
(1) 200g (S)-ibuprofen, 800g phosphatidylinositols, 500g cholesterol, 300g stigmasterol and 600g polyoxyl 40 hydrogenated castor oil being dissolved in the 120000ml volume ratio is in 3: 1 the ethanol and acetone mixed solvent, mix homogeneously, organic solvent is removed in decompression on rotary film evaporator, obtains lipid membrane;
(2) under nitrogen protection, add the 15000ml pH value in the bottle and be 6.5 phosphate buffered solution, jolting, stirred 30 minutes, rotating speed is 400-700r/min, makes the complete aquation of immobilized artificial membrane, with the homogeneous emulsifying 10-15 of tissue mashing machine's high speed minute, rotating speed 5000r/min with 0.45 μ m filtering with microporous membrane, makes liposome turbid liquor;
(3) with above-mentioned liposome turbid liquor spray drying, make (S)-ibuprofen liposome powder;
(4) (S)-ibuprofen liposome powder and 125g lactose, 80g microcrystalline Cellulose, 20g polyvinylpolypyrrolidone are mixed, cross 80 mesh sieve mix homogeneously, 50% the ethanol water 100ml that adds 10% xanthan gum prepares soft material, crosses 20 mesh sieves and granulates drying;
(5) with dried granule and 5g zinc stearate mix homogeneously, cross 20 mesh sieve granulate;
(6) tabletting makes 1000 (S)-ibuprofen liposome sheets.
The preparation of embodiment 2 (S)-ibuprofen liposome tablets
Used supplementary material is as follows:
Adopt following production technology to prepare (S)-ibuprofen liposome sheet:
(1) 200g (S)-ibuprofen, 1200g phosphatidylinositols, 500g cholesterol, 300g stigmasterol and 700g polyoxyl 40 hydrogenated castor oil being dissolved in the 150000ml volume ratio is in 3: 1 the ethanol and acetone mixed solvent, mix homogeneously, organic solvent is removed in decompression on rotary film evaporator, obtains lipid membrane;
(2) under nitrogen protection, add the 18000ml pH value in the bottle and be 6.5 phosphate buffered solution, jolting, stirred 30 minutes, rotating speed is 400-700r/min, makes the complete aquation of immobilized artificial membrane, with the homogeneous emulsifying 10-15 of tissue mashing machine's high speed minute, rotating speed 5000r/min with 0.45 μ m filtering with microporous membrane, makes liposome turbid liquor;
(3) with above-mentioned liposome turbid liquor spray drying, make (S)-ibuprofen liposome powder;
(4) (S)-ibuprofen liposome powder and 200g lactose, 100g microcrystalline Cellulose, 130g polyvinylpolypyrrolidone are mixed, cross 80 mesh sieve mix homogeneously, 50% the alcoholic solution 200ml that adds 20% xanthan gum prepares soft material, crosses 20 mesh sieves and granulates drying;
(5) with dried granule and 20g zinc stearate mix homogeneously, cross 20 mesh sieve granulate;
(6) tabletting makes 1000 (S)-ibuprofen liposome tablets.
The preparation of embodiment 3 (S)-ibuprofen liposome methods
Used supplementary material is as follows:
Adopt following production technology to prepare the (S)-ibuprofen liposome methods:
(1) 150g (S)-ibuprofen, 1125g phosphatidylinositols, 450g cholesterol, 300g stigmasterol and 600g polyoxyl 40 hydrogenated castor oil being dissolved in the 200000ml volume ratio is in 3: 1 the ethanol and acetone mixed solvent, mix homogeneously, organic solvent is removed in decompression on rotary film evaporator, obtains lipid membrane;
(2) under nitrogen protection, add the 20000ml pH value in the bottle and be 6.5 phosphate buffered solution, jolting, stirred 30 minutes, rotating speed is 400-700r/min, makes the complete aquation of immobilized artificial membrane, with the homogeneous emulsifying 10-15 of tissue mashing machine's high speed minute, rotating speed 5000r/min with 0.45 μ m filtering with microporous membrane, makes liposome turbid liquor;
(3) with above-mentioned liposome turbid liquor spray drying, make (S)-ibuprofen liposome powder;
(4) (S)-ibuprofen liposome powder and 150g lactose, 150g microcrystalline Cellulose, 120g polyvinylpolypyrrolidone are mixed, cross 80 mesh sieve mix homogeneously, 50% the alcoholic solution 300ml that adds 25% xanthan gum prepares soft material, crosses 20 mesh sieves and granulates drying;
(5) with dried granule and 7.5g zinc stearate mix homogeneously, cross 20 mesh sieve granulate;
(6) filled capsules makes 1000 (S)-ibuprofen liposome methods.
Comparative Examples 1-3
Adopt with respectively with embodiment 1-3 in identical production technology, the supplementary material composition among the Comparative Examples 1-3 as shown in following table 1 (Comparative Examples 3 is CN102198132A embodiment 2 similar prescriptions) is made respectively (S)-ibuprofen liposome sheet and capsule:
Used supplementary material composition among the table 1 Comparative Examples 1-3
The comparative example 4
Take by weighing 6.0mg (S)-ibuprofen, 15.0mg Ovum Gallus domesticus Flavus lecithin, 3.0mg cholesterol, 3.0mg vitamin C, make their dissolvings with the chloroform/methanol (mass ratio 4: 1) of 6.0g, and mix homogeneously obtains solution.Mentioned solution is placed Rotary Evaporators, and chloroform and methanol are removed in distilling under reduced pressure, make lipid film.Be that 6 phosphate buffer joins in the lipid film with pH, rotating 4h on the Rotary Evaporators in 20 ℃ of temperature are bathed, behind the ultrasonic 5min of water-bath, the filter membrane of crossing 22 μ m makes the (S)-ibuprofen liposome.
Wherein, "/" expression is not used.
The investigation of test example 1 liposome
The prepared liposomal samples of step (3) among embodiment 1-3 and the Comparative Examples 1-3 is carried out quality investigation, mainly carry out liposome morphologic observation, particle size determination and liposome encapsulation and measure.
Wherein, liposome morphologic observation and particle size determination adopt optical microscopy and the computing of statistica5.0 statistical software to observe about 1000 liposomees to average.
Entrapment efficiency determination adopts column chromatography for separation in conjunction with spectrophotometry, the method operating procedure is: use column chromatography the liposome in the drug solution is separated, utilize ethanol to destroy the liposome bilayer, calculate envelop rate with HPLC method and standard control again after making drug release out, by formula Q
Ooze%=(W
Bag-W
Storage)/W
Bag* 100% calculates percolation ratio.
The results are shown in the following table 2.
The investigation result of table 2 liposome
As shown in Table 2, gained (S)-ibuprofen liposome form rule among the embodiment of the invention 1-3, the size homogeneous, mean diameter is little, and envelop rate is higher, and percolation ratio is low; And gained (S)-ibuprofen liposome form is irregular among the Comparative Examples 1-4, and mean diameter is large, and envelop rate is low, and percolation ratio is high.
Particularly, even when adopting same production technology, particle appearance, mean diameter, envelop rate and the percolation ratio of gained (S)-ibuprofen liposome obviously are better than respectively the (S)-ibuprofen liposome of gained among the Comparative Examples 1-3 among the embodiment 1-3.This shows that perhaps when the composition consumption was outside the composition amount ranges that the present invention limits, the quality of gained (S)-ibuprofen liposome obviously was inferior to the present invention when the composition beyond the used composition of use the present invention.
Test example 2 stability and dissolution are investigated
With the Pidotimod liposome solid preparation sample of above embodiment 1-3 preparation and the (S)-ibuprofen sheet (Jiangxi Huiren Pharmaceutical Co., Ltd of listing, lot number 20101103) 40 ℃ of high temperature, lower 6 months of relative humidity 75% ± 5% condition, carry out accelerated test and investigate, the results are shown in the following table 3.
Table 3 accelerated test result
As shown in Table 3, when accelerating June, listing preparation dissolution reduces, content, and related substance raises; And that sample dissolution of the present invention, content and related substance change is all not obvious, illustrates that the product of the present invention preparation that goes on the market has higher stability.
Test example 3 dissolution tests are investigated
Pidotimod liposome solid preparation sample prepared among embodiment 1-3 and the Comparative Examples 1-3 has been carried out the release inspection.This test is carried out according to the first method in 2010 editions appendix XD of Chinese Pharmacopoeia drug release determination method, and each sample result of the test of statistics has been made release profiles, and sampling time point is in this experiment: 2,4,8,12,16 hours, the results are shown in the following table 4:
The release data of table 4 (S)-ibuprofen
Draw respectively release profiles according to table 4, be shown among Fig. 1,
Wherein, curve 1 is the (S)-ibuprofen release profiles of prepared sample among the embodiment 1;
Curve 3 is the (S)-ibuprofen release profiles of prepared sample among the embodiment 3;
Curve 5 is the (S)-ibuprofen release profiles of prepared sample in the Comparative Examples 2;
As shown in Figure 1, Pidotimod liposome solid preparation of the present invention (below among the figure) discharges slowly, reach good slow release effect, and Comparative Examples Pidotimod liposome solid preparation slow release effect is poor.This shows that perhaps when the composition consumption was outside the composition amount ranges that the present invention limits, the slow release effect of gained Pidotimod liposome solid preparation was inferior to the present invention when the composition beyond the used composition of use the present invention.
In sum, the present invention selects (S)-ibuprofen, phosphatidylinositols, cholesterol, stigmasterol and the polyoxyl 40 hydrogenated castor oil of specified weight proportioning, makes the (S)-ibuprofen liposome of excellent quality, has obtained unexpected wonderful synergy.
Industrial applicibility
By the result of above-described embodiment and experimental example as can be known, Pidotimod liposome solid preparation of the present invention has good outward appearance, and granule is little, and particle diameter is even, envelop rate is high, and stability is high, and percolation ratio is low, the time of staying in vivo is long, and bioavailability is high, has good industrial application value.
Below through the specific embodiment and the embodiment the present invention is had been described in detail; but should understand; these explanations do not consist of any restriction to scope of the present invention; in the case of without departing from the spirit and scope of protection of the present invention; can carry out multiple modification, improvement and replacement to technical solutions and their implementation methods of the present invention, these are all because falling within the scope of protection of the present invention.
Claims (4)
1. (S)-ibuprofen liposome, it is made by the composition that comprises following weight proportion:
And weight sum and the weight ratio between the phosphatidylinositols of cholesterol and stigmasterol are 1:1-1:1.5;
The preparation method of wherein said (S)-ibuprofen liposome may further comprise the steps:
(a) (S)-ibuprofen, phosphatidylinositols, cholesterol, stigmasterol and polyoxyl 40 hydrogenated castor oil are dissolved in the organic solvent, mix homogeneously, organic solvent is removed in decompression on rotary film evaporator, obtains lipid membrane;
(b) under nitrogen protection, in bottle, add buffer solution, jolting was stirred 30 minutes, rotating speed was 400-700r/min, makes the complete aquation of immobilized artificial membrane, with the homogeneous emulsifying 10-15 of tissue mashing machine's high speed minute, rotating speed 5000r/min with 0.45 μ m filtering with microporous membrane, makes liposome turbid liquor;
(c) with above-mentioned liposome turbid liquor spray drying, make (S)-ibuprofen liposome powder;
And wherein organic solvent described in the step (a) is that volume ratio is the ethanol of 3:1 and the mixed solvent of acetone; Buffer solution described in the step (b) is that pH value is 6.5 phosphate buffered solution.
2. Pidotimod liposome solid preparation, it is made by (S)-ibuprofen liposome claimed in claim 1 and other pharmaceutic adjuvants, wherein, based on the (S)-ibuprofen of 1 weight portion, described other pharmaceutic adjuvants and amount thereof are diluent: lactose 0.5-1 part and microcrystalline Cellulose 0.3-1 part, disintegrating agent: polyvinylpolypyrrolidone 0.1-0.8 part, binding agent: xanthan gum 0.05-0.5 part and lubricant: zinc stearate 0.02-0.05 part.
3. Pidotimod liposome solid preparation according to claim 2, it is the Tablet and Capsula agent.
4. the preparation method of each described Pidotimod liposome solid preparation according to claim 2-3, the method may further comprise the steps:
(1) preparation of (S)-ibuprofen liposome: (S)-ibuprofen and phosphatidylinositols, cholesterol, stigmasterol and polyoxyl 40 hydrogenated castor oil are mixed with the liposome powder;
(2) preparation of Pidotimod liposome solid preparation: the (S)-ibuprofen liposome is mixed with other pharmaceutic adjuvants, the preparation Pidotimod liposome solid preparation, wherein said other pharmaceutic adjuvant is diluent: lactose 0.5-1 part and microcrystalline Cellulose 0.3-1 part, disintegrating agent: polyvinylpolypyrrolidone 0.1-0.8 part, binding agent: xanthan gum 0.05-0.5 part and lubricant: zinc stearate 0.02-0.05 part;
And the preparation of step (1) (S)-ibuprofen liposome comprises following substep:
(a) (S)-ibuprofen, phosphatidylinositols, cholesterol, stigmasterol and polyoxyl 40 hydrogenated castor oil are dissolved in the organic solvent, mix homogeneously, organic solvent is removed in decompression on rotary film evaporator, obtains lipid membrane;
(b) under nitrogen protection, in bottle, add buffer solution, jolting was stirred 30 minutes, rotating speed was 400-700r/min, makes the complete aquation of immobilized artificial membrane, with the homogeneous emulsifying 10-15 of tissue mashing machine's high speed minute, rotating speed 5000r/min with 0.45 μ m filtering with microporous membrane, makes liposome turbid liquor;
(c) with above-mentioned liposome turbid liquor spray drying, make (S)-ibuprofen liposome powder;
Wherein, organic solvent described in the step (a) is that volume ratio is the ethanol of 3:1 and the mixed solvent of acetone; Buffer solution described in the step (b) is that pH value is 6.5 phosphate buffered solution;
The preparation of step (2) Pidotimod liposome solid preparation comprises following substep:
(d) (S)-ibuprofen liposome powder and diluent, disintegrating agent are mixed, cross 80 mesh sieve mix homogeneously, add binder solution and prepare soft material, cross 20 mesh sieves and granulate drying;
(e) dried granule and mix lubricant is even, cross 20 mesh sieve granulate;
(f) tabletting or filled capsules make Pidotimod liposome solid preparation.
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| US10561627B2 (en) | 2014-12-31 | 2020-02-18 | Eric Morrison | Ibuprofen nanoparticle carriers encapsulated with hermetic surfactant films |
| US11007161B1 (en) | 2014-12-31 | 2021-05-18 | Eric Morrison | Ibuprofen nanoparticle carriers encapsulated with hermatic surfactant films |
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| CN113304250A (en) * | 2003-11-20 | 2021-08-27 | 诺和诺德股份有限公司 | Propylene glycol-containing peptide formulations optimized for production and use in injection devices |
| CA2897874A1 (en) * | 2013-01-14 | 2014-07-17 | Infirst Healthcare Limited | Compositions and methods for treating severe pain |
| CN105935445B (en) * | 2016-03-28 | 2019-02-01 | 赤峰赛林泰药业有限公司 | Pharmaceutical composition and preparation method thereof containing 2- (- 4- isobutyl phenenyl) propionic acid dextrogyre |
| CN105878268A (en) * | 2016-04-07 | 2016-08-24 | 梁海东 | Pharmaceutic preparation for treating osteoarthritis |
| CN105853446A (en) * | 2016-04-07 | 2016-08-17 | 梁海东 | Medicine preparation for treating osteoarthritis and preparation method thereof |
| EP4360651A3 (en) | 2017-08-24 | 2024-07-17 | Novo Nordisk A/S | Glp-1 compositions and uses thereof |
| CN108186570B (en) * | 2018-02-09 | 2019-11-26 | 张恩景 | A kind of (S)-ibuprofen liposome and its preparation method and application |
| CN109157862B (en) * | 2018-08-24 | 2020-10-27 | 天津大学 | Mixed solution capable of separating out microspheres under action of highly converged laser beam |
| CA3165355A1 (en) | 2020-02-18 | 2021-07-22 | Tommy SANDER | Pharmaceutical formulations |
| CN116370428A (en) * | 2023-04-28 | 2023-07-04 | 济南市中西医结合医院 | Ibuprofen sustained release tablet, preparation method and application |
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| DE4447287C1 (en) * | 1994-12-30 | 1996-11-07 | Cevc Gregor | Droplet-in-fluid composition to transport agent e.g. through skin |
| US5827533A (en) * | 1997-02-06 | 1998-10-27 | Duke University | Liposomes containing active agents aggregated with lipid surfactants |
| EP2123258A1 (en) * | 2008-05-23 | 2009-11-25 | Liplasome Pharma A/S | Liposomes for drug delivery |
| ES2330295B1 (en) * | 2008-06-06 | 2010-09-23 | Laboratorios Alcala Farma, Sl | TOPIC FORMULATION OF IBUPROFEN. |
| CN101797230B (en) * | 2010-04-19 | 2012-08-01 | 王明 | Liposome solid preparation of losartan potassium hydrochlorothiazide pharmaceutical composition |
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| US10561627B2 (en) | 2014-12-31 | 2020-02-18 | Eric Morrison | Ibuprofen nanoparticle carriers encapsulated with hermetic surfactant films |
| US11007161B1 (en) | 2014-12-31 | 2021-05-18 | Eric Morrison | Ibuprofen nanoparticle carriers encapsulated with hermatic surfactant films |
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