CN102440958B - Ibuprofen sodium liposome solid preparation and preparation method thereof - Google Patents
Ibuprofen sodium liposome solid preparation and preparation method thereof Download PDFInfo
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- CN102440958B CN102440958B CN 201110387592 CN201110387592A CN102440958B CN 102440958 B CN102440958 B CN 102440958B CN 201110387592 CN201110387592 CN 201110387592 CN 201110387592 A CN201110387592 A CN 201110387592A CN 102440958 B CN102440958 B CN 102440958B
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Abstract
The invention discloses an ibuprofen sodium liposome solid preparation and a preparation method thereof. According to the invention, ibuprofen sodium, dispermaceti phosphate, phosphatidylcholine, cholesterol and tween 80 at a specific weight ratio are selected to prepare ibuprofen sodium liposome with excellent quality, and the solid preparation is prepared from the liposome by using an ordinary preparation method. Compared to conventional preparations, the preparation provided in the invention has the following advantages: stability and bioavailability of the preparation are substantially improved, the quality of the preparation is enhanced, toxic and side effects are reduced, and a more remarkable curative effect is obtained.
Description
Technical field
The present invention relates to a kind of novel formulation of Sodium ibuprofen, be specifically related to a kind of Sodium ibuprofen liposome and solid preparation and method for making, belong to medical technical field.
Background technology
Ibuprofen, be that 2-(4-isobutyl phenenyl) propanoic acid is a kind of known medicine with analgesia, antiinflammatory reconciliation thermal characteristics, it is used in particular for treating inflammatory diseases and anti-pain, such as rheumatism, headache, migraine, toothache, backache, myalgia, postoperative pain etc.Its treatment effective form is S (+)-ibuprofen, and R (-)-enantiomer is nearly unavailable, but it can partly be converted into effective S (+)-form in vivo.
Sodium ibuprofen is a kind of medicine with analgesia, antiinflammatory reconciliation thermal characteristics, and it is used in particular for treating inflammatory diseases and anti-pain, such as rheumatism, headache, migraine, toothache, backache, myalgia, postoperative pain etc.The analgesia of Sodium ibuprofen, antiinflammation mechanism are illustrated not yet fully, may act on the inflammation tissue local, work by suppressing the synthetic of prostaglandin or other mediators, because it is suppressed that leukocyte activity and lysosomal enzyme discharge, make the pain sensation impulsion of tissue local reduce the Reduced susceptibility of pain receptor.The treatment gout is by antiinflammatory, analgesia, can not corrects hyperuricemia.The mechanism of action for the treatment of dysmenorrhea may be that synthetic being suppressed of prostaglandin reduced intra-uterine pressure decline, uterine contraction.
The therapeutic effect of Sodium ibuprofen depends on the design to its pharmaceutical preparation to a great extent.Importantly, the form of the Sodium ibuprofen chemical compound of pro ore medicine should provide high bioavailability, reaches maximization so that Sodium ibuprofen enters the absorption of blood, and the amount that is retained in the Sodium ibuprofen in the gastrointestinal tract reaches and minimizes.
The Sodium ibuprofen preparation of at present external list marketing mainly contains tablet, capsule and granule, but above-mentioned preparation toxic and side effects is more obvious, and long-term shelf-stability is not high, has affected clinical practice.
According to the document of having delivered, the solid dosage forms that is made by Sodium ibuprofen take advantage aspect the pharmacokinetics (that is, they can more promptly enter blood flow and reach peak value than other solid dosage forms of ibuprofen).Yet, although in this field deep research is arranged, use conventional method to form solid dosage forms by Sodium ibuprofen and still have any problem.
One of difficulty is that the flow behavior of Sodium ibuprofen is poor, therefore even when with conventional anti-caking agent blend such as silica gel or Talcum also often lumps easily.Namely use flow improving agent to prepare, the relatively poor flow behavior of Sodium ibuprofen also may cause producing unsettled weight change in the made solid dosage forms such as tablet and capsule tablet.
Another difficulty that forms the Sodium ibuprofen tablet is that Sodium ibuprofen tends to form film coating at the punch head surface of rotary tablet machine.Because this film coating reduces brightness or the gloss of institute's tablet that forms or capsule tablet, although so when inexcessive, this film coating also is worthless.If form too much coating at punch head surface, can run into many operating difficultiess.At first, can defective appear at formed tablet or capsule tablet.Secondly, can cause the unstable of drift operation.The 3rd, also may produce the weight change of unacceptable tablet.
On the other hand, the dihydrate of the fragrant sodium in Lip river almost no longer has hygroscopicity, only absorbs the water less than 0.5% weight under the relative humidity level of room temperature, 90%RH again.For example, the sodium ibuprofen hydrate of water content in the 13-14% weight range is open under 40 ℃ and 75%RH stores no longer suction more than 6 months.Quite commonly, Sodium ibuprofen during from the manufacturer shipment water content unsuitable with dihydrate because lose easily water of crystallization when dry and this material drying becomes the monohydrate form easily down at 40-50 ℃.
Therefore, find a kind of method that forms the Sodium ibuprofen compositions, especially find a kind of method of the solid preparation by Sodium ibuprofen preparation also to be very important.
Patent documentation CN102099017A discloses a kind of high-load Sodium ibuprofen granule, its preparation and the purposes in the non-effervescent solid dosage forms of preparation thereof.Be specifically related to the high-load ibuprofen pharmacy particle that made by Sodium ibuprofen monocalcium salt compound, relate to the method and technology for preparing this granule, and relate to the purposes of this granule in preparation non-effervescent solid dosage forms for oral use.Yet the Sodium ibuprofen preparation of said method preparation is prepared although screened specific adjuvant, and having must advantage; But the dissolution of medicine and bioavailability still remain to be improved, and the long-time stability of medicine are undesirable, are unfavorable for long-term storage.
Liposome 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.
Conventional 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.
If Sodium ibuprofen can be made liposome, then be expected to overcome the series of problems that existing Sodium ibuprofen preparation exists, improve dissolubility and the stability of medicine, prolong drug retention time in vivo, improve bioavailability, reduce toxic and side effects, improve treatment speed and therapeutic effect.
Although relevant ibuprofen prepares the record of liposome in the prior art, such as the disclosure of CN1411803A the load of lyophobic and modified glucan modified liposome to many kinds of substances such as ibuprofen.CN1703199A has disclosed that Schramlova etc. (Folia Biol (Praha) 43:195-199,1997) has united ibuprofen and from the liposome of soybean phospholipid and cholesterol preparation.
But, the challenge of preparation liposome is to select suitable liposome constituent and method for making.Because the character of liposome is directly closely related with the composition of liposome 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 kind of excipient composition to form the Sodium ibuprofen liposome with better quality is the present invention's difficult problem in the urgent need to address.
The applicant finds by a large amount of experiments, the lipidosome solid preparation that adopts particular excipient and Sodium ibuprofen to make has not only overcome the problem of principal agent poor stability effectively, greatly improve simultaneously the dissolution of medicine, delayed to discharge, increased medicine retention time in vivo
Summary of the invention
One of purpose of the present invention provides a kind of stable pharmaceutical composition that comprises Sodium ibuprofen.
The inventor is through for a long time in earnest research, unexpectedly find to be applied to contain a kind of liposome of targeting drug delivery system in the solid preparation of Sodium ibuprofen, the targeting that not only can strengthen principal agent can also improve preparation drug effect and bioavailability, simultaneously improve widely the stability of active component in the preparation, got unforeseeable technique effect.
One of purpose of the present invention provides a kind of Sodium ibuprofen Liposomal formulation, is mainly made by Sodium ibuprofen, phospholipid, additives.
In the context of the present invention, statement " Sodium ibuprofen " comprises the sodium salt of the mixture of the sodium salt of the sodium salt of raceme ibuprofen and enantiomer S (+)-ibuprofen and R (-)-ibuprofen and these enantiomer.Preferred S (+)-sodium ibuprofen hydrate and the particularly racemic sodium ibuprofen hydrate used.
Preparation lipidosome injection membrane material commonly used is phospholipid and additives, wherein phospholipid can be selected natural phospholipid and synthetic phospholipid usually, and described natural phospholipid is one or more in Ovum Gallus domesticus Flavus lecithin, hydrogenation egg yolk lecithin, EPG, egg yolk lecithin acyl serine, PI, soybean lecithin, hydrogenated soya phosphatide, soybean phospholipid acyl glycerol, soy phosphatidylserine, the soybean phospholipid acyl inositol; Described synthetic phospholipid is one or more in DOPC, DSPC, dipalmitoyl phosphatidyl choline, dimyristoyl phosphatidyl choline, DLPC, DOPG, DSPG, DPPG, GLYCEROL,DIMYRISTOYL PHOSPHATIDYL, the PE.The membrane material of additives commonly used has cholesterol, 18-amine., phosphatidic acid, sodium deoxycholate and PLURONICS F87.Membrane material for the preparation of lipidosome injection also has PHOSPHATIDYL ETHANOLAMINE, cholesterol second fat, paddy to carry alcohol, natrii tauroglycocholas, phosphatidyl silk amino acid, stearmide, single stearoyl phosphatidic acid, single stearoyl PHOSPHATIDYL ETHANOLAMINE, two cetyl phosphate (DCP), DPPE, single palmityl PHOSPHATIDYL ETHANOLAMINE, two myristoyl PHOSPHATIDYL ETHANOLAMINE.Additives generally are used for regulating membrane structure, change charged character, such as cholesterol the liposome bi-layer membrane are solidified, thereby reduce the generation of free radical, have reduced oxidation level, and liposome stability is significantly strengthened.
The inventor finds through creative research, by Sodium ibuprofen, two Cetyl Phosphates, lecithin, cholesterol and the Tween 80 of selecting the specified weight proportioning, can form the Sodium ibuprofen liposome of excellent quality, again liposome is made solid preparation with general formulation method, thereby finish the present invention.
In Sodium ibuprofen liposome of the present invention, for the Sodium ibuprofen of 200 weight portions, the consumption of two Cetyl Phosphates is the 25-150 weight portion, and the consumption of lecithin is the 25-150 weight portion.If the consumption of two Cetyl Phosphates or lecithin is lower than 25 weight portions, it is not encapsulated to have a large amount of free Sodium ibuprofens, and the drug loading of liposome is low, and stability also can descend; Otherwise if the consumption of two Cetyl Phosphates or lecithin is higher than 150 weight portions, then the envelop rate as the Sodium ibuprofen of active constituents of medicine descends.
In Sodium ibuprofen liposome of the present invention, cholesterol and Tween 80 are used for regulating the membrane stability of liposome.
Cholesterol is a kind of amphiphilic, combines with two Cetyl Phosphates and lecithin, stops it to be condensed into crystal structure.Cholesterol mixes in two Cetyl Phosphates and the Lecithin Bilayer Membranes, 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.
Studies show that the stability of liposome and bioavailability have close corresponding relation.Stability is higher, and bioavailability is higher.Therefore, the stability of Sodium 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 Sodium ibuprofen liposome of the present invention, for the Sodium ibuprofen of 200 weight portions, the consumption of two Cetyl Phosphates is the 25-150 weight portion, the consumption of lecithin is the 25-150 weight portion, and when cholesterol was the 50-200 weight portion, the envelop rate of formed Sodium ibuprofen liposome was high.
In Sodium ibuprofen liposome of the present invention, further change stability and the envelop rate of liposome membrane with Tween 80.Tween 80 is a kind of non-ionic surface active agent, when being used for two Cetyl Phosphates and Lecithin Bilayer Membranes, can not only further improve the dissolubility of Sodium ibuprofen, thereby improves envelop rate; And can improve chemical energy between this duplicature, thus the chemical stability of liposome in waterborne liquid improved, and then improve the stability of Sodium ibuprofen.
In Sodium ibuprofen liposome of the present invention, for the Sodium ibuprofen of 200 weight portions, the consumption of Tween 80 is the 25-200 weight portion.If the consumption of Tween 80 is lower than 25 weight portions, then cause owing to its consumption is excessively low stability and the envelop rate of liposome are improved not, otherwise, if the consumption of Tween 80 is higher than 200 weight portions, then causes liposome membrane to be easy to destroy owing to its consumption is too high and reveal active component.
In Sodium ibuprofen liposome of the present invention, cholesterol by an amount of proportioning and Tween 80 are to the collaborative adjusting facilitation of two Cetyl Phosphates and lecithin membrane structure, can form envelop rate height, stable high Sodium ibuprofen liposome, its had good sustained release effect, bioavailability is high.
The inventor is through long-term conscientious research, through a large amount of screening tests, find to adopt general phospholipid and additives be the liposome of film material preparation under the accelerated test of 40 ℃ of high temperature, relative humidity 75% ± 5%, stability and envelop rate are not good.The combination of unexpected discovery two Cetyl Phosphates of the inventor, lecithin, cholesterol and four kinds of materials of Tween 80, stability and the not good problem of envelop rate of liposome have been solved, obtained beyond thought preparation effect, thereby superior in quality liposome is provided.
Particularly, the invention provides a kind of Sodium ibuprofen liposome, mainly is to be made by the following composition based on the weight portion meter:
Preferably, two Cetyl Phosphates are 1: 1 with the ratio of the weight of lecithin, and the weight sum of two Cetyl Phosphates and lecithin is 1: 1～3: 1 with the ratio of the weight of cholesterol.
Further preferably, Sodium ibuprofen liposome provided by the invention is mainly made by the composition of following weight proportion:
Preferably, two Cetyl Phosphates are 1: 1 with the ratio of the weight of lecithin, and the weight sum of two Cetyl Phosphates and lecithin is 1: 1～2: 1 with the ratio of the weight of cholesterol.
Another object of the present invention provides a kind of method for making of Sodium ibuprofen liposome, and the method may further comprise the steps:
(a) Sodium ibuprofen, two Cetyl Phosphates, lecithin, cholesterol and Tween 80 are dissolved in the organic solvent, stir and make its dissolving;
(b) mentioned solution is placed eggplant-shape bottle, organic solvent is removed in 50 ℃ of water-bath decompressions, forms uniformly transparent film at the bottle wall;
(c) in eggplant-shape bottle, add buffer solution, continue to make the films swell hydration 50 ℃ of water-bath normal pressure rotations;
(d) with mentioned solution with 0.45 μ m filtering with microporous membrane, filtrate is placed-20 ℃ of refrigerator and cooled freeze and spends the night, then take out to melt, spray drying makes Sodium ibuprofen liposome powder.
Preferably, (d) with mentioned solution with 0.45 μ m filtering with microporous membrane, filtrate is placed-20 ℃ of refrigerator and cooled freeze and spends the night, then take out to melt, multigelation three times, spray drying makes Sodium ibuprofen liposome powder.
In a preferred embodiment of Sodium ibuprofen liposome method for making 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, acetonitrile, the normal hexane, is preferably ethanol;
In a preferred embodiment of Sodium ibuprofen liposome method for making 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 7.2 carbonate buffer solution.
By said method, can prepare the little and uniform Sodium 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.Sodium 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.
One of purpose of the present invention provides a kind of solid preparation that contains the Sodium ibuprofen liposome, has equally good bioavailability.
Sodium ibuprofen lipidosome solid preparation provided by the invention, wherein, the specification of the Sodium ibuprofen lipidosome solid preparation of unit dose is 200mg and 400mg.
The solid preparation that contains the Sodium ibuprofen liposome of the present invention is comprised of Sodium ibuprofen liposome described above and pharmaceutically acceptable other excipient, such as solid preparations such as tablet, effervescent tablet, capsule and granules.
The Sodium ibuprofen solid preparation that the present invention is described above, wherein said excipient is not particularly limited, and can be the pharmaceutic adjuvant of solid preparation commonly used in the pharmaceutics.
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.
As concrete enforcement, specifically made by following component by weight:
1 part of Sodium ibuprofen liposome, filler 0.14-0.34 part, disintegrating agent 0.01-0.04 part, binding agent 0.01-0.02 part, correctives 0.02-0.03 part and lubricant 0.007-0.01 part.
In a preferred embodiment of Sodium ibuprofen lipidosome solid preparation of the present invention, described filler is selected from one or more in starch, lactose, mannitol, sorbitol, dextrin and the sucrose, is preferably starch, mannitol and sucrose.
In a preferred embodiment of Sodium ibuprofen lipidosome solid preparation of the present invention, described disintegrating agent is selected from one or more of low-substituted hydroxypropyl cellulose, carboxymethylstach sodium, cross-linking sodium carboxymethyl cellulose, sodium bicarbonate, potassium bicarbonate, citric acid, polyvinylpolypyrrolidone, one or more in preferred cross-linking sodium carboxymethyl cellulose, sodium bicarbonate, potassium bicarbonate and the citric acid.
In a preferred embodiment of Sodium ibuprofen lipidosome solid preparation of the present invention, described binding agent is selected from one or more in PVP K30, hypromellose, sodium carboxymethyl cellulose, arabic gum, xanthan gum, methylcellulose and the ethyl cellulose, is preferably methylcellulose.
In a preferred embodiment of Sodium ibuprofen lipidosome solid preparation of the present invention, described lubricant is selected from one or more in magnesium stearate, zinc stearate, Pulvis Talci, Macrogol 4000, the stearic acid, is preferably zinc stearate.
In a preferred embodiment of Sodium ibuprofen lipidosome solid preparation of the present invention, binder solution is 40% alcoholic solution.
In a preferred embodiment of Sodium ibuprofen lipidosome solid preparation of the present invention, correctives is selected from Fructus Citri tangerinae essence, acesulfame potassium, aspartame.
Sodium ibuprofen lipidosome solid preparation provided by the invention is oral formulations, comprises tablet, effervescent tablet, capsule and granule.
In practice, consider the effective dose of medicine and the convenience of medication, in the preferred embodiment of Sodium ibuprofen lipidosome solid preparation of the present invention, the specification of preparation is that per unit preparation Sodium ibuprofen is 200mg or 400mg.
A further object of the present invention provides the method for making of above-mentioned a kind of Sodium ibuprofen lipidosome solid preparation, and the method may further comprise the steps:
(e) Sodium ibuprofen liposome powder and diluent, disintegrating agent and binding agent are mixed, the mix homogeneously that sieves adds wetting agent and prepares soft material, the granulation of sieving, drying;
(f) dried granule and mix lubricant is even, granulate sieves;
(g) tabletting, filled capsules or pack make the Sodium ibuprofen lipidosome solid preparation.
Compare with existing preparation technique, Sodium ibuprofen lipidosome solid preparation provided by the invention has improved preparation stripping property, stability and bioavailability greatly; Reduce toxic and side effects, improved the formulation products quality, improved therapeutic effect.
The present invention first combination of the specified weight by active component Sodium ibuprofen and two Cetyl Phosphates, lecithin, cholesterol and Tween 80 is prepared into liposome, is mixed and made into solid preparation with other pharmaceutic adjuvant again.The solid preparation product quality is high, and particle diameter is even, and stability is high, and envelop rate is high, and medicine retention time in blood circulation is long, and is evident in efficacy; Used adjuvant cheap and simple is polluted little.
The preparation method of Sodium ibuprofen lipidosome solid preparation provided by the invention has improved product quality, and equipment is simple, easy operating, and industrialized great production is highly advantageous to.
In this article, if not especially explanation, content or consumption are all by weight.
Description of drawings
Below, describe by reference to the accompanying drawings embodiment of the present invention in detail, wherein:
Fig. 1 is the release profiles of Sodium ibuprofen in the preparation of the present invention.
The specific 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.
Embodiment 1The preparation of Sodium ibuprofen liposome sheet
Adopt following production technology to prepare Sodium ibuprofen liposome sheet:
(a) 200g Sodium ibuprofen, 100g two Cetyl Phosphates, 100g lecithin, 100g cholesterol and 100g Tween 80 are dissolved in the 2000ml ethanol, stir and make its dissolving;
(b) mentioned solution is placed eggplant-shape bottle, ethanol is removed in 50 ℃ of water-bath decompressions, forms uniformly transparent film at the bottle wall;
(c) adding the 2000ml pH value in the eggplant-shape bottle is 7.2 carbonate buffer solution, continues to make the films swell hydration 50 ℃ of water-bath normal pressures rotations;
(d) with mentioned solution with 0.45 μ m filtering with microporous membrane, filtrate is placed-20 ℃ of refrigerator and cooled freeze and spends the night, then take out to melt, multigelation three times, spray drying makes Sodium ibuprofen liposome powder.
(e) Sodium ibuprofen liposome powder and 200g starch, 10g cross-linking sodium carboxymethyl cellulose, 10g methylcellulose are mixed, cross 80 mesh sieve mix homogeneously, the alcoholic solution that adds 100ml40% prepares soft material, crosses 20 mesh sieves and granulates drying;
(f) with dried granule and 5g zinc stearate mix homogeneously, granulate sieves;
(g) tabletting makes 1000 Sodium ibuprofen liposome sheets.
Embodiment 2The preparation of Sodium ibuprofen liposome methods
Adopt following production technology to prepare the Sodium ibuprofen liposome methods:
(a) 200g Sodium ibuprofen, 125g two Cetyl Phosphates, 125g lecithin, 150g cholesterol and 50g Tween 80 are dissolved in the 2000ml ethanol, stir and make its dissolving;
(b) mentioned solution is placed eggplant-shape bottle, ethanol is removed in 50 ℃ of water-bath decompressions, forms uniformly transparent film at the bottle wall;
(c) adding 2000mlpH value in the eggplant-shape bottle is 7.2 carbonate buffer solution, continues to rotate at 50 ℃ of water-bath normal pressures, makes the films swell hydration;
(d) with mentioned solution with 0.45 μ m filtering with microporous membrane, filtrate is placed-20 ℃ of refrigerator and cooled freeze and spends the night, then take out to melt, multigelation three times, spray drying makes Sodium ibuprofen liposome powder.
(e) Sodium ibuprofen liposome powder and 150g starch, 20g cross-linking sodium carboxymethyl cellulose, 10g methylcellulose are mixed, cross 80 mesh sieve mix homogeneously, the alcoholic solution that adds 100ml40% prepares soft material, crosses 20 mesh sieves and granulates drying;
(f) with dried granule and 5g zinc stearate mix homogeneously, granulate sieves;
(g) filled capsules makes 1000 Sodium ibuprofen liposome methods.
Embodiment 3The preparation of Sodium ibuprofen liposome effervescent tablet
Adopt following production technology to prepare Sodium ibuprofen liposome effervescent tablet:
(a) 400g Sodium ibuprofen, 100g two Cetyl Phosphates, 100g lecithin, 100g cholesterol and 50g Tween 80 are dissolved in the 2000ml ethanol, stir and make its dissolving;
(b) mentioned solution is placed eggplant-shape bottle, ethanol is removed in 50 ℃ of water-bath decompressions, forms uniformly transparent film at the bottle wall;
(c) adding 2000mlpH value in the eggplant-shape bottle is 7.2 carbonate buffer solution, continues to rotate at 50 ℃ of water-bath normal pressures, makes the films swell hydration;
(d) with mentioned solution with 0.45 μ m filtering with microporous membrane, filtrate is placed-20 ℃ of refrigerator and cooled freeze and spends the night, then take out to melt, multigelation three times, spray drying makes Sodium ibuprofen liposome powder.
(e) Sodium ibuprofen liposome powder and 100g mannitol, 60g citric acid, 35g sodium bicarbonate, 15g acesulfame potassium and 5g aspartame are mixed, cross 80 mesh sieve mix homogeneously, the alcoholic solution that adds 100ml40% prepares soft material, crosses 20 mesh sieves and granulates drying;
(f) with dried granule and 5g zinc stearate mix homogeneously, granulate sieves;
(g) tabletting makes 1000 Sodium ibuprofen liposome effervescent tablets.
Embodiment 4The preparation of Sodium ibuprofen liposome particles agent
Adopt following production technology to prepare the Sodium ibuprofen liposome particles:
(a) 400g Sodium ibuprofen, 150g two Cetyl Phosphates, 150g lecithin, 150g cholesterol and 100g Tween 80 are dissolved in the 2000ml ethanol, stir and make its dissolving;
(b) mentioned solution is placed eggplant-shape bottle, ethanol is removed in 50 ℃ of water-bath decompressions, forms uniformly transparent film at the bottle wall;
(c) adding 2000mlpH value in the eggplant-shape bottle is 7.2 carbonate buffer solution, continues to rotate at 50 ℃ of water-bath normal pressures, makes the films swell hydration;
(d) with mentioned solution with 0.45 μ m filtering with microporous membrane, filtrate is placed-20 ℃ of refrigerator and cooled freeze and spends the night, then take out to melt, multigelation three times, spray drying makes Sodium ibuprofen liposome powder.
(e) Sodium ibuprofen liposome powder and 150g sucrose, 60g sodium bicarbonate, 10g acesulfame potassium, 10g aspartame are mixed, cross 80 mesh sieve mix homogeneously, the alcoholic solution that adds the 100ml40% that is dissolved with 5g Fructus Citri tangerinae essence prepares soft material, crosses 20 mesh sieves and granulates drying;
(f) with dried granule and 5g zinc stearate mix homogeneously, granulate sieves;
(g) pack makes 1000 bags of ibuprofen sodium lipidosome granules.
Comparative Examples 1-4
Supplementary material composition in will the Comparative Examples 1-4 as shown in following table 1, adopt respectively with embodiment 1-4 in identical production technology make Sodium ibuprofen liposome tablet, effervescent tablet, capsule and granule:
Raw materials used composition among the table 1 Comparative Examples 1-4
Wherein, "/" expression is not used.
Test example 1The investigation of liposome
The prepared lipidosome solid sample of step (d) among embodiment 1-4 and the Comparative Examples 1-4 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 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 Tween 80 to destroy the liposome bilayer, calculate envelop rate with HPLC method and standard control again after making drug release out, ooze %=(W by formula Q
Bag-W
Storage)/W
Bag* 100% calculates percolation ratio.
The results are shown in the following table 2.
Table 2 liposome is investigated the result
As shown in Table 2, gained Sodium ibuprofen liposome form rule among the embodiment of the invention 1-4, the size homogeneous, mean diameter is little, and envelop rate is higher, and percolation ratio is low; And gained Sodium 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, compare with Comparative Examples 1,2, gained liposome outward appearance rule among the embodiment 1,2, mean diameter is little, and envelop rate is high, and seepage is low.This shows that when the composition beyond the used composition of use the present invention, the quality of gained Sodium ibuprofen liposome obviously is inferior to the present invention.
Particularly, even when adopting same production technology, compare with Comparative Examples 3,4, gained liposome outward appearance rule among the embodiment 3,4, mean diameter is little, and envelop rate is high, and seepage is low.This shows that when the composition consumption was outside the composition amount ranges that the present invention limits, the quality of gained Sodium ibuprofen liposome obviously was inferior to the present invention.
Test example 2Stability and dissolution are investigated
With the Sodium ibuprofen sheet (Reckitt Benckiser Healthcare (UK) Ltd) of the Sodium ibuprofen lipidosome solid preparation sample for preparing among embodiment and the Comparative Examples 1-4 and external listing under the condition of 40 ℃ of high temperature, relative humidity 75% 6 months, 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, the Sodium ibuprofen sheet of listing and the sample dissolution of Comparative Examples are low, and content is obvious when accelerating June, and its related substances raises; And the sample dissolution of embodiment of the invention preparation is high, accelerates that content and related substance have no significant change after June, proves absolutely that the present invention is at the superiority that improves aspect stability and the dissolution.
Test example 3Dissolution test is investigated
Sodium ibuprofen lipidosome solid preparation sample prepared among embodiment 1-4 and the Comparative Examples 1-4 has been carried out the release investigation.This test is carried out according to the first method in 2010 editions appendix XD of Chinese Pharmacopoeia drug release determination sample, and each sample result of the test of statistics has been made release profiles.
Sampling time point is in this test: 1,2,4,6,8 hours, the results are shown in accompanying drawing 1.
Wherein, curve 1 expression embodiment 1 Sodium ibuprofen release profiles; Curve 2 expression embodiment 2 Sodium ibuprofen release profiles; Curve 3 expression embodiment 3 Sodium ibuprofen release profiles; Example 4 Sodium ibuprofen release profiles are executed in curve 4 expressions; Curve 5 expression Comparative Examples 1 Sodium ibuprofen release profiles; Curve 6 expression Comparative Examples 2 Sodium ibuprofen release profiles; Curve 7 expression Comparative Examples 3 Sodium ibuprofen release profiles; Curve 8 expression Comparative Examples 4 Sodium ibuprofen release profiles.
As shown in Figure 1, the Sodium ibuprofen releasing effect of sample of the present invention is better than Comparative Examples.
This shows that stability and the vitro release of Sodium ibuprofen lipidosome solid preparation of the present invention are better than Comparative Examples, have improved stability and releasing effect.
Industrial applicibility
By the result of above-described embodiment and experimental example as can be known, Sodium ibuprofen lipidosome 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.
Each list of references of mentioning among the application or quoting, which is hereby incorporated by reference.
Claims (11)
1. Sodium ibuprofen liposome is characterized in that being made by the following composition based on the weight portion meter:
Wherein, two Cetyl Phosphates are 1: 1 with the ratio of the weight of lecithin, and the weight sum of two Cetyl Phosphates and lecithin is 1: 1～3: 1 with the ratio of the weight of cholesterol.
2. according to claim 1 Sodium ibuprofen liposome is characterized in that being made by the following composition based on the weight portion meter:
Wherein, two Cetyl Phosphates are 1: 1 with the ratio of the weight of lecithin, and the weight sum of two Cetyl Phosphates and lecithin is 1: 1～2: 1 with the ratio of the weight of cholesterol.
3. method for preparing the Sodium ibuprofen liposome of claim 1 or 2 is characterized in that may further comprise the steps:
(a) Sodium ibuprofen, two Cetyl Phosphates, lecithin, cholesterol and Tween 80 are dissolved in the organic solvent, stir and make its dissolving;
(b) mentioned solution is placed eggplant-shape bottle, organic solvent is removed in 50 ℃ of water-bath decompressions, forms uniformly transparent film at the bottle wall;
(c) in eggplant-shape bottle, add buffer solution, continue to make the films swell hydration 50 ℃ of water-bath normal pressure rotations;
(d) with mentioned solution with 0.45 μ m filtering with microporous membrane, filtrate is placed-20 ℃ of refrigerator and cooled freeze and spends the night, then take out to melt, multigelation three times, spray drying makes Sodium ibuprofen liposome powder.
4. solid preparation that contains the Sodium ibuprofen liposome is characterized in that being comprised of claim 1 or 2 described Sodium ibuprofen liposomees and pharmaceutically acceptable other excipient
5. solid preparation according to claim 4 is characterized in that being selected from tablet, effervescent tablet, capsule and granule.
6. according to claim 4 or 5 solid preparation, it is characterized in that pharmaceutically acceptable other excipient are selected from filler, disintegrating agent, binding agent, correctives and lubricant.
7. method for preparing Sodium ibuprofen lipidosome solid preparation as claimed in claim 6 is characterized in that said method comprising the steps of:
(e) Sodium ibuprofen liposome powder and diluent, disintegrating agent and binding agent are mixed, the mix homogeneously that sieves adds wetting agent and prepares soft material, the granulation of sieving, drying;
(f) dried granule and mix lubricant is even, granulate sieves;
(g) tabletting, filled capsules or pack make the Sodium ibuprofen lipidosome solid preparation.
8. the application of Sodium ibuprofen liposome claimed in claim 1 in the medicine of preparation analgesia, antiinflammatory reconciliation thermal characteristics.
9. application according to claim 8, wherein said medicine is used for the treatment of rheumatism, headache, migraine, toothache, backache, myalgia, postoperative pain.
10. the application of Sodium ibuprofen lipidosome solid preparation claimed in claim 4 in the medicine of preparation analgesia, antiinflammatory reconciliation thermal characteristics.
11. application according to claim 10, wherein said medicine is used for the treatment of rheumatism, headache, migraine, toothache, backache, myalgia, postoperative pain.
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