CN102440959A - Pidotimod liposome solid preparation - Google Patents
Pidotimod liposome solid preparation Download PDFInfo
- Publication number
- CN102440959A CN102440959A CN2011103881163A CN201110388116A CN102440959A CN 102440959 A CN102440959 A CN 102440959A CN 2011103881163 A CN2011103881163 A CN 2011103881163A CN 201110388116 A CN201110388116 A CN 201110388116A CN 102440959 A CN102440959 A CN 102440959A
- Authority
- CN
- China
- Prior art keywords
- pidotimod
- liposome
- solid preparation
- cholesterol
- weight ratio
- 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.)
- Granted
Links
Images
Abstract
The invention discloses a pidotimod liposome solid preparation and its preparation method. According to the invention, pidotimod, hydrogenated soya phosphatide, cholesterol, soybean sterol and tween 80 with specific weight ratio are selected to prepare the pidotimod liposome with excellent quality, and then the pidotimod liposome can be prepared to the solid preparation by a general preparation method. The provided liposome solid preparation has the characteristics of high encapsulation rate, uniform particle size and long retention time of medicine in blood circulation; and the preparation method has the advantages of simple equipment and easy operation, is capable of raising the product quality and minimizing the toxic and side effect, and is suitable for large industrial production.
Description
Technical field
The present invention relates to a kind of pidotimod novel formulation, be specifically related to a kind of pidotimod lipidosome solid preparation, belong to medical technical field.
Background technology
Pidotimod (Pidotimod) is successfully synthesized in the later stage eighties 20th century by Italian POLI chemical industrial company, and with got permission listing in 1993 and be used for clinical.Its chemistry (R)-3-[(S)-(5-oxo-2-pyrrolidinyl) carbonyl] by name-tetrahydro-thiazoles-4-carboxylic acid, molecular formula:
Pidotimod is the dipeptide medicine of synthetic, is a kind of promoter of immunologic function safely and effectively, can promote nonspecific immune reaction, can promote specific immune response again.It can promote the activate the phagocytic capacity of macrophage and neutrophilic granulocyte, improves its chemotaxis; Activate natural killer cell; The former lymphopoiesis that causes of mitosis promoting, the helper T lymphocyte that reduces when making immunologic hypofunction (CD4+) raises recovery normally with the ratio of suppressor T lymphocyte (CD8+); Through stimulating interleukin-2 and beta-interferon to promote cell immune response.Though all showing pidotimod, clinical experiment do not have directly antibiotic and antiviral activity; But the immunologic function of passing through to promote human body is to antibacterial (streptococcus pneumoniae; Escherichia coli, bacillus pyocyaneus, Bacillus proteus) and virus (popular virus; Herpes simplex virus, murine encephalomyocarditis virus and Mengo virus etc.) infect and bring into play significant curative effect.
Being mainly used in the treatment disease of immunodeficiency aspects such as respiratory repeated infection, department of otorhinolaryngology repeated infection, urinary system infection and adjuvant therapy of malignant tumor up and down clinically, is the significant immunopotentiating agent of a kind of treatment.The intravenous injection pidotimod is applicable to the patient of inconvenient oral administration, and rapid-action, and bioavailability is high.
Pidotimod is widely used having now in the technology, and for example patent documentation CN1868464A discloses a kind of Piduomode soft capsule preparation and preparation method thereof that comprises, its one or more with in active component pidotimod and diluent, cosolvent, solubilizing agent, suspending agent, the surfactant; The mixed content that gets; Adopt the soft capsule preparation method to prepare soft capsule, soft capsule is washed ball, is done eventually with appropriate solvent through solidifying by cooling in wind, drying; Both; The soft capsule practicality that this then method makes is restricted, and retention cycle is shorter, and bioavailability is lower.
Patent documentation CN101011362A discloses a kind of dispersible tablet of pidotimod and method for preparing and application; Having improved prescription forms and method for preparing; Though it is easy that this dispersible tablet is taken; But its rate of release and lasting releasability remain further to be improved, and the low shortcoming of solid preparation bioavailability of traditional method preparation still exists.
Patent documentation CN101422445A discloses a kind of pidotimod effervescent tablets; Though it is easy that this disintegrating tablet is taken; But its rate of release and lasting releasability remain further to be improved; And contain sodium bicarbonate and organic acid in its sheet, and bad person is inapplicable to gastrointestinal tract, and its bioavailability also has much room for improvement.
Patent documentation CN101234096A discloses a kind of pidotimod capsule preparation and preparation method thereof, but the bioavailability of conventional capsules agent is low.
Though the pidotimod class pharmaceutical dosage form of above-mentioned present listing has screened specific adjuvant and has prepared; Having must advantage, but the long-time stability of medicine are undesirable, are unfavorable for long-term storage; Drug releasing rate and drug release process can not be controlled, thereby bring hidden danger can for clinical use; And the pidotimod bioavailability is low.
Liposome is meant drug encapsulation made spherical targeted drug carrier formulation of superminiature in the middle of the thin film that the lipoids bimolecular forms, and belongs to a kind of novel form of targeting drug delivery system.Liposome has plurality of advantages as pharmaceutical carrier: can seal fat-soluble medicine like liposome, can seal water soluble drug again; Alleviate allergy and immunoreation; Delay to discharge, reduce elimination speed in the body; Can protect the medicine that is wrapped effectively, improve bioavailability; Change medicine distribution in vivo, and can the release of targeting property, the toxic and side effects of medicine can be reduced; Be fit to multipath administration etc.
The main mechanism of action of conventional liposome is that drug powder or solution are wrapped in the aqueous phase that the liposome bilayer lipid membrane sealed or embed in the liposome bilayer lipid membrane; This microgranule type of having cellularity; Get into the interior principal agent of human body is activated body by reticuloendothelial system phagocytic autoimmune function; And change is distributed in the body of entrapped drug; Drug main to be put aside in histoorgans such as liver, spleen, lung and bone marrow, thereby improve the therapeutic index of medicine, reduce the therapeutic dose and the toxicity that reduces medicine of medicine.
In order to improve the stability of pidotimod, improve bioavailability, strengthen its targeting property, the inventor studies the pidotimod lipidosome solid preparation.Find that through a large amount of experiments the lipidosome solid preparation that adopts particular excipient and pidotimod to process has effectively overcome the problem of principal agent poor stability, improved the dissolution of medicine simultaneously, increased medicine retention time in vivo.
Summary of the invention
To achieve these goals, big quantity research and realization that the inventor carries out find that pidotimod, hydrogenated soya phosphatide, cholesterol, soyasterol and the Tween 80 of specified weight proportioning can be processed the pidotimod liposome; Wherein, high as the envelop rate of the pidotimod of active constituents of medicine, the liposome particle diameter is little and be evenly distributed; The retention time significant prolongation of pidotimod in the gained solid preparation in the body circulation; The raising of targeting property, bioavailability obviously improves, and curative effect obviously improves.
One of the object of the invention provides a kind of pidotimod liposome, and it is mainly processed by following components by weight ratio:
Preferably, the weight sum of cholesterol and soyasterol and the weight ratio between the hydrogenated soya phosphatide are 1: 1-1: 4.
More particularly, pidotimod liposome according to the invention, mainly process by following components by weight ratio:
Preferably, the weight sum of cholesterol and soyasterol and the weight ratio between the hydrogenated soya phosphatide are 1: 1-1: 2.
Most preferably, pidotimod liposome according to the invention, mainly process by following components by weight ratio:
Wherein, the weight sum of cholesterol and soyasterol and the weight ratio between the hydrogenated soya phosphatide 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, Ovum Gallus domesticus Flavus lecithin, hydrogenation egg yolk lecithin, EPG, egg yolk lecithin acyl serine, egg yolk lecithin acyl inositol, hydrogenated soya phosphatide, soybean lecithin, PHOSPHATIDYL ETHANOLAMINE, soybean phospholipid acyl glycerol, soy phosphatidylserine and soybean phospholipid acyl inositol etc.Synthetic phospholipid be the dioleoyl phospholipid phatidylcholine,, dipalmitoyl phosphatidyl choline, two myristoyl phosphatidylcholines, two Laurel phosphatidyl cholines, DOPG, distearyl phosphatidyl glycerol, DSPC, two palmityl phosphatidyl glycerols, GLYCEROL,DIMYRISTOYL PHOSPHATIDYL, two lauroyl phosphatidyl glycerols etc.
Inventor's process discovers that hydrogenated soya phosphatide is particularly suitable for sealing pidotimod as basic immobilized artificial membrane material, thereby forms liposome.Hydrogenated soya phosphatide is a kind of natural phospholipid, is easy to form the stabilized liposomes film.When using other phospholipid, be difficult to form colory liposome, character such as the envelop rate of liposome, stability and percolation ratio are poor.
In pidotimod liposome of the present invention, for the pidotimod of 1 weight portion, the consumption of hydrogenated soya phosphatide is the 0.1-6 weight portion.If the consumption of hydrogenated soya phosphatide is lower than 0.1 weight portion, have a large amount of free pidotimods and do not sealed, the drug loading of liposome is low; Otherwise if the consumption of hydrogenated soya phosphatide is higher than 6 weight portions, then the envelop rate as the pidotimod of active constituents of medicine descends.
In pidotimod liposome of the present invention, cholesterol and soyasterol and Tween 80 are used to regulate the membrane stability of liposome.
Cholesterol is a kind of amphiphilic, combines with hydrogenated soya phosphatide, stops it to be condensed into crystal structure.Cholesterol mixes in the hydrogenated soya phosphatide 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 liposome bimolecular tunic solidify, thereby reduces the generation of free radical, reduces oxidation level, and liposome stability is significantly strengthened.
Soyasterol is that soyasterol is from the concise product of soybean oil, to extract the plant sterol that forms, and is without any side effects, is cholesterol reducing, prevents and treats cardiovascular disease, anticancer desirable material.As a kind of natural product, the soyasterol source is abundant, low price.
With cholesterol seemingly, soyasterol also can be regulated the stability of hydrogenated soya phosphatide film, and its regulating action effect to stability is superior to cholesterol.
The inventor is through discovering, when the weight sum and the hydrogenated soya phosphatide weight ratio of cholesterol and soyasterol is 1: 1-1: in the time of 4, can form stable pidotimod liposome.When the weight sum of cholesterol and soyasterol and hydrogenated soya phosphatide weight ratio were higher than 1: 1, membrane stability reduced, and pidotimod is easy to seepage; When the weight sum of cholesterol and soyasterol and hydrogenated soya phosphatide weight ratio were lower than 1: 4, pidotimod liposome membrane flowability was too high, is wrapped in the intravital pidotimod of lipid and is easy to discharge.In addition, discover that when the weight sum and the hydrogenated soya phosphatide weight ratio of cholesterol and soyasterol is 1: 1-1: in the time of 4, formed liposome toxicity is low.
Research shows that the stability of liposome and bioavailability have close corresponding relation.Stability is high more, and bioavailability is high more.Therefore, the stability of pidotimod liposome of the present invention is high, is to cause one of high factor of drug bioavailability.
In addition, the inventor discovers, in pidotimod liposome of the present invention; For the pidotimod of 1 weight portion; The consumption of hydrogenated soya phosphatide is the 0.1-6 weight portion, and cholesterol is the 0.05-1.0 weight portion, and soyasterol is the 0.05-0.5 weight portion; And the weight sum of cholesterol and soyasterol and hydrogenated soya phosphatide weight ratio are 1: 1-1: 4 o'clock, the envelop rate of formed pidotimod liposome was high.
In pidotimod liposome of the present invention, use Tween 80 further to improve the stability of liposome membrane.Tween 80 (polysorbate 80) is a kind of non-ionic surface active agent; When being used for the hydrogenated soya phosphatide duplicature; Can improve the chemical energy between this duplicature, thereby improve the chemical stability of liposome in waterborne liquid, and then improve the stability of pidotimod liposome.
In pidotimod liposome of the present invention, for the pidotimod of 1 weight portion, the consumption of Tween 80 is the 0.1-1 weight portion.If the consumption of Tween 80 is lower than 0.1 weight portion, then since its consumption low excessively cause the stability improvement of pidotimod liposome not enough, otherwise if the consumption of Tween 80 is higher than 1 weight portion, it is too high and cause liposome membrane to be easy to reveal then to be used for its consumption.
Discover, when the pidotimod that uses above-mentioned specified quantitative, hydrogenated soya phosphatide, cholesterol, soyasterol and Tween 80, can obtain colory pidotimod liposome; Its envelop rate and stability are all very high, and toxicity is low, and rate of release is low; Targeting property is high, and bioavailability is high.
Another object of the present invention provides the method for preparing of above-mentioned pidotimod liposome, and this method may further comprise the steps:
(a) pidotimod, hydrogenated soya phosphatide, cholesterol, soyasterol and Tween 80 are dissolved in the organic solvent, mix homogeneously, organic solvent is removed in decompression on rotary film evaporator, obtains lipid membrane;
(b) add buffer solution, jolting was stirred 30 minutes, and rotating speed is 400-700r/min, makes the complete aquation of immobilized artificial membrane, with the even at a high speed matter emulsifying of tissue mashing machine 10-15 minute, and rotating speed 5000r/min, 0.45 μ m filtering with microporous membrane makes liposome turbid liquor;
(c), make pidotimod liposome powder with above-mentioned liposome turbid liquor spray drying.
In an embodiment preferred of pidotimod 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 5: 1 the tert-butyl alcohol and the mixed solvent of acetone.
In an embodiment preferred of pidotimod 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, and preferred pH value is 6.5 PBS.
Through said method, can prepare the little and uniform pidotimod liposome of particle size distribution of granule, its envelop rate is high, and stability is high, is difficult for leaking, and bioavailability is high.
Discover that the size of liposome is to influence the liposome principal element with the time of staying that distributes in vivo, the particle diameter of liposome is more little, and the time of staying is long more in the body.Pidotimod liposome particles through the inventive method preparation is little, and particle size distribution is even, and this is one of its factor that metabolic rate is low in vivo, bioavailability is high.
Another object of the present invention provides a kind of pidotimod lipidosome solid preparation, and it is processed by pidotimod liposome and other pharmaceutic adjuvants.
As one of concrete embodiment, based on the pidotimod of 1 weight portion, the amount of other pharmaceutic adjuvants is 0.5-5 part.
Pidotimod lipidosome solid preparation according to the invention mainly is an oral formulations, comprises tablet, capsule and granule.
In an embodiment preferred of pidotimod lipidosome solid preparation of the present invention, based on the pidotimod of 1 weight portion, the amount of other pharmaceutic adjuvants is the 1-4.2 weight portion.
In this article; The meaning of used term " other pharmaceutic adjuvants " or " pharmaceutic adjuvant " and excipient equivalent in meaning; Be meant the medicinal material except the pidotimod liposome that uses in order to prepare the pidotimod lipidosome solid preparation, comprise diluent, disintegrating agent, sweeting agent, binding agent, lubricant and combination thereof.
In this article, used term " amounts of other pharmaceutic adjuvants " is meant the weight sum of above-mentioned pharmaceutic adjuvant.
The consumption of various pharmaceutic adjuvants can be selected according to the general consumption of each adjuvant in solid preparation by those skilled in the art, and this is in those skilled in the art's limit of power.
As one of concrete embodiment, pidotimod lipidosome solid preparation of the present invention, mainly process by following component by weight:
1 part of pidotimod liposome, diluent 0.4-1.5 part, disintegrating agent 0.05-0.5 part, sweeting agent 0-1 part, lubricant 0.0125-0.05 part and binding agent 0.025-0.125 part.
In an embodiment preferred of pidotimod lipidosome solid preparation of the present invention, diluent is selected from one or more in starch, pregelatinized Starch, lactose, sorbitol, microcrystalline Cellulose, the dextrin, is preferably starch and microcrystalline Cellulose.
In an embodiment preferred of pidotimod lipidosome 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 an embodiment preferred of pidotimod lipidosome solid preparation of the present invention, sweeting agent is selected from sucrose, mannitol, Aspartane, saccharin sodium, sucralose, stevioside, the steviosin and their combination, is preferably Aspartane.
In an embodiment preferred of pidotimod lipidosome solid preparation of the present invention; Binding agent is selected from a kind of in 30 POVIDONE K 30 BP/USP 30, starch slurry, hypromellose, sodium carboxymethyl cellulose, ethyl cellulose, arabic gum, the xanthan gum, is preferably arabic gum.
In an embodiment preferred of pidotimod lipidosome solid preparation of the present invention, adhesive solvent is selected from the alcoholic solution of 20-70%, preferred 35% alcoholic solution.
In an embodiment preferred of pidotimod lipidosome 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.
As one of embodiment more specifically, pidotimod lipidosome solid preparation of the present invention, mainly process by following component by weight:
1 part of pidotimod liposome, starch and microcrystalline Cellulose 0.4-1.5 part, polyvinylpolypyrrolidone 0.05-0.5 part, aspartame 0-1 part, arabic gum 0.025-0.125 part, zinc stearate 0.0125-0.05 part and 35% alcoholic solution are an amount of.
Pidotimod lipidosome solid preparation provided by the invention is an oral formulations, comprises tablet, capsule and granule.Its specification is that per unit preparation pidotimod is 400mg.
Another object of the present invention provides the method for preparing of above-mentioned pidotimod lipidosome solid preparation, and this method may further comprise the steps:
(d) pidotimod 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, filled capsules or pack make the pidotimod lipidosome solid preparation.
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, like heat sterilization, filtration sterilization, radiation sterilization or sterile working etc.
Advantage of the present invention:
Pidotimod lipidosome solid preparation provided by the invention has improved the bioavailability of pidotimod; 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; And method for preparing is simple, is suitable for industrialized great production.
In this article, if not explanation especially, content or consumption are all by weight.
Description of drawings
Below, specify embodiment of the present invention in conjunction with accompanying drawing, wherein:
Fig. 1 is the release profiles of pidotimod in the pidotimod lipidosome solid preparation.
The specific embodiment
Below through concrete preferred embodiment the present invention is further specified.These embodiment only are illustrative, and should not be construed as limitation of the present invention.
Embodiment 1The preparation of pidotimod liposome sheet
Used supplementary material is following:
Adopt following production technology to prepare pidotimod liposome sheet:
(1) 400g pidotimod, 150g hydrogenated soya phosphatide, 50g cholesterol, 50g soyasterol and 50g Tween 80 being dissolved in the 1000ml volume ratio is in 5: 1 the tert-butyl alcohol and acetone mixed solvent; Mix homogeneously; Organic solvent is removed in decompression on rotary film evaporator, obtains lipid membrane;
(2) adding 1000ml pH value is 6.5 PBS, and jolting was stirred 30 minutes; Rotating speed was 400-700r/min, makes the complete aquation of immobilized artificial membrane, with the even at a high speed matter emulsifying of tissue mashing machine 10-15 minute; Rotating speed 5000r/min, 0.45 μ m filtering with microporous membrane makes liposome turbid liquor;
(3), make pidotimod liposome powder with above-mentioned liposome turbid liquor spray drying;
(4) pidotimod liposome powder and 125g starch, 50g microcrystalline Cellulose, 20g polyvinylpolypyrrolidone are mixed, cross 80 mesh sieve mix homogeneously, 35% the alcoholic solution 100ml that adds 10% arabic gum prepares soft material, crosses 20 mesh sieves and granulates drying;
(5), cross 20 mesh sieve granulate with dried granule and 5g zinc stearate mix homogeneously;
(6) tabletting makes 1000 pidotimod liposome sheets.
Embodiment 2The preparation of pidotimod liposome particles agent
Used supplementary material is following:
Adopt following production technology to prepare the pidotimod liposome particles:
(1) 400g pidotimod, 300g hydrogenated soya phosphatide, 150g cholesterol, 150g soyasterol and 200g Tween 80 being dissolved in the 1500ml volume ratio is in 5: 1 the tert-butyl alcohol and acetone mixed solvent; Mix homogeneously; Organic solvent is removed in decompression on rotary film evaporator, obtains lipid membrane;
(2) adding 1000ml pH value is 6.5 PBS, and jolting was stirred 30 minutes; Rotating speed was 400-700r/min, makes the complete aquation of immobilized artificial membrane, with the even at a high speed matter emulsifying of tissue mashing machine 10-15 minute; Rotating speed 5000r/min, 0.45 μ m filtering with microporous membrane makes liposome turbid liquor;
(3), make pidotimod liposome powder with above-mentioned liposome turbid liquor spray drying;
(4) with pidotimod liposome powder and 400g starch, 200g microcrystalline Cellulose, 130g polyvinylpolypyrrolidone mix, the 80g aspartame; Cross 80 mesh sieve mix homogeneously; 35% the alcoholic solution 200ml that adds 25% arabic gum prepares soft material, crosses 20 mesh sieves and granulates drying;
(5), cross 20 mesh sieve granulate with dried granule and 20g zinc stearate mix homogeneously;
(6) pack makes 1000 bags of pidotimod liposome particles.
Embodiment 3The preparation of pidotimod liposome methods
Used supplementary material is following:
Adopt following production technology to prepare the pidotimod liposome methods:
(1) 400g pidotimod, 300g hydrogenated soya phosphatide, 100g cholesterol, 150g soyasterol and 150g Tween 80 being dissolved in the 1500ml volume ratio is in 5: 1 the tert-butyl alcohol and acetone mixed solvent; Mix homogeneously; Organic solvent is removed in decompression on rotary film evaporator, obtains lipid membrane;
(2) adding 1500ml pH value is 6.5 PBS, and jolting was stirred 30 minutes; Rotating speed was 400-700r/min, makes the complete aquation of immobilized artificial membrane, with the even at a high speed matter emulsifying of tissue mashing machine 10-15 minute; Rotating speed 5000r/min, 0.45 μ m filtering with microporous membrane makes liposome turbid liquor;
(3), make pidotimod liposome powder with above-mentioned liposome turbid liquor spray drying;
(4) pidotimod liposome powder and 400g starch, 200g microcrystalline Cellulose, 60g polyvinylpolypyrrolidone are mixed, cross 80 mesh sieve mix homogeneously, 35% the alcoholic solution 200ml that adds 5% arabic gum prepares soft material, crosses 20 mesh sieves and granulates drying;
(5), cross 20 mesh sieve granulate with dried granule and 10g zinc stearate mix homogeneously;
(6) filled capsules makes 1000 pidotimod liposome methods.
Comparative Examples 1-3
Composition in will the Comparative Examples 1-3 shown in following table 1, adopt respectively with embodiment 1-3 in identical production technology, process pidotimod liposome sheet, granule and capsule:
Raw materials used composition among the table 1 Comparative Examples 1-3
Wherein, "/" expression is not used.
Test Example 1The investigation of 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 to average.
Entrapment efficiency determination adopts column chromatography for separation to combine spectrophotometry; This method operating procedure is: use column chromatography the liposome in the drug solution is separated; Utilize sorbester p17 to destroy the liposome bilayer; Calculate envelop rate with HPLC method and standard control again after medicine is discharged, ooze %=(W bag-W storage)/W bag * 100% by formula Q and calculate percolation ratio.
The result is shown in the following table 2.
The investigation result of table 2 liposome
Can know by table 2, gained pidotimod 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 pidotimod liposome form is irregular among the Comparative Examples 1-3, and mean diameter is big, 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 pidotimod liposome obviously are superior to the pidotimod liposome of gained among the Comparative Examples 1-3 respectively among the embodiment 1-3.When this showed the composition beyond using the used composition of the present invention, perhaps when the composition consumption was outside the composition amount ranges that the present invention limits, the quality of gained pidotimod liposome obviously was inferior to the present invention.
Test Example 2Stability and dissolution are investigated
With above embodiment and the pidotimod lipidosome solid preparation sample of Comparative Examples 1-3 preparation and pidotimod sheet (Taiyangshi (Tangshan) Pharm Ind Co., Ltd. of listing; Lot number 20100418) 40 ℃ of high temperature; Following 6 months of relative humidity 75% ± 5% condition; Carry out accelerated test and investigate, the result is shown in the following table 3.
Table 3 accelerated test result
Can be known that by table 3 when quickening June, listing preparation and Comparative Examples preparation dissolution reduce, content reduces, and related substance raises; And that sample dissolution of the present invention, content and related substance change is all not obvious, explains that the product of the present invention preparation that goes on the market has higher stability.
Test Example 3The test of release degree is investigated
Pidotimod lipidosome solid preparation sample prepared among embodiment 1-3 and the Comparative Examples 1-3 has been carried out the inspection of release degree.This test is carried out according to 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: 1,2,4,6,8 hours, the result was shown in the following table 4:
The release data of table 4 pidotimod
Draw release profiles respectively according to table 4, be shown among Fig. 1.
Can know that by Fig. 1 pidotimod lipidosome solid preparation of the present invention discharges slowly, reach the good slow release effect, and Comparative Examples pidotimod lipidosome solid preparation slow release effect is poor.When this showed the composition beyond using the used composition of the present invention, perhaps when the composition consumption was outside the composition amount ranges that the present invention limits, the slow release effect of gained pidotimod lipidosome solid preparation was inferior to the present invention.
Industrial applicibility
Result by the foregoing description and experimental example can know that pidotimod lipidosome solid preparation of the present invention has good surface 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 the favorable industrial using value.
More than through the specific embodiment and embodiment the present invention is specified; But should understand; These explanations do not constitute any restriction to scope of the present invention; Under the situation that does not depart from spirit of the present invention and protection domain, can carry out multiple modification, improvement and replacement to technical scheme of the present invention and embodiment thereof, these are all because of falling in protection scope of the present invention.
Claims (10)
1. pidotimod liposome is characterized in that mainly being processed by following components by weight ratio:
Preferably, the weight sum of cholesterol and soyasterol and the weight ratio between the hydrogenated soya phosphatide are 1: 1-1: 4.
2. pidotimod liposome according to claim 1 is characterized in that mainly being processed by following components by weight ratio:
Preferably, the weight sum of cholesterol and soyasterol and the weight ratio between the hydrogenated soya phosphatide are 1: 1-1: 2.
3. pidotimod liposome according to claim 2 is characterized in that mainly being processed by following components by weight ratio:
Preferably, the weight sum of cholesterol and soyasterol and the weight ratio between the hydrogenated soya phosphatide are 1: 1-1: 1.5.
4. the method for preparing of each described pidotimod liposome among the claim 1-3 is characterized in that may further comprise the steps:
(a) pidotimod, hydrogenated soya phosphatide, cholesterol, soyasterol and Tween 80 are dissolved in the organic solvent, mix homogeneously, organic solvent is removed in decompression on rotary film evaporator, obtains lipid membrane;
(b) add buffer solution, jolting was stirred 30 minutes, and rotating speed is 400-700r/min, makes the complete aquation of immobilized artificial membrane, with the even at a high speed matter emulsifying of tissue mashing machine 10-15 minute, and rotating speed 5000r/min, 0.45 μ m filtering with microporous membrane makes liposome turbid liquor;
(c), make pidotimod liposome powder with above-mentioned liposome turbid liquor spray drying.
5. method according to claim 4; It is characterized in that; 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 5: 1 the tert-butyl alcohol and the mixed solvent of acetone;
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, and preferred pH value is 6.5 PBS.
6. pidotimod lipidosome solid preparation; It is characterized in that processing by each described pidotimod liposome among the claim 1-3 and other pharmaceutic adjuvants, wherein, based on the pidotimod of 1 weight portion; The amount of other pharmaceutic adjuvants is 0.5-5 part, preferred 1-4.2 part.
7. pidotimod lipidosome solid preparation according to claim 6 is characterized in that said other pharmaceutic adjuvants comprise diluent, disintegrating agent, sweeting agent, binding agent, lubricant and combination thereof.
8. pidotimod lipidosome solid preparation according to claim 6 is characterized in that said solid preparation comprises tablet, capsule or granule.
9. according to the method for preparing of each described pidotimod lipidosome solid preparation among the claim 6-8, this method may further comprise the steps:
(d) pidotimod 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, filled capsules or pack make the pidotimod lipidosome solid preparation.
10. the pidotimod lipidosome solid preparation of the pidotimod liposome of claim 1 and claim 6 is in the preparation treatment purposes in the medicine of the disease aspect the immunodeficiencies such as respiratory repeated infection, department of otorhinolaryngology repeated infection, urinary system infection and adjuvant therapy of malignant tumor up and down.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201110388116 CN102440959B (en) | 2011-11-29 | 2011-11-29 | Pidotimod liposome solid preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201110388116 CN102440959B (en) | 2011-11-29 | 2011-11-29 | Pidotimod liposome solid preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102440959A true CN102440959A (en) | 2012-05-09 |
| CN102440959B CN102440959B (en) | 2013-01-23 |
Family
ID=46004221
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 201110388116 Expired - Fee Related CN102440959B (en) | 2011-11-29 | 2011-11-29 | Pidotimod liposome solid preparation |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102440959B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114224905A (en) * | 2020-09-09 | 2022-03-25 | 杭州星鳌生物科技有限公司 | Application of pidotimod and natural immune agonist compound in preparation of anti-tumor drugs and other drugs |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998022114A1 (en) * | 1996-11-15 | 1998-05-28 | Dumex-Alpharma A/S | A method for promoting tissue repair |
-
2011
- 2011-11-29 CN CN 201110388116 patent/CN102440959B/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998022114A1 (en) * | 1996-11-15 | 1998-05-28 | Dumex-Alpharma A/S | A method for promoting tissue repair |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114224905A (en) * | 2020-09-09 | 2022-03-25 | 杭州星鳌生物科技有限公司 | Application of pidotimod and natural immune agonist compound in preparation of anti-tumor drugs and other drugs |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102440959B (en) | 2013-01-23 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102579350B (en) | Pidotimod liposome solid preparation | |
| WO2014101356A1 (en) | Gamabufotalin liposome, preparation method therefor and applicationthereof | |
| CN102614182B (en) | Solid preparation of compound ammonia phenol renin medicine composition liposome | |
| CN102166208B (en) | Lisinopril and hydrochlorothiazide pharmaceutical composition liposome solid preparation | |
| CN102440959B (en) | Pidotimod liposome solid preparation | |
| CN102335133B (en) | Cefaclor lipidosome solid preparation | |
| CN102716098B (en) | Cefditoren pivoxil liposome solid preparation | |
| CN102138899B (en) | Olmesartan liposome solid preparation | |
| CN102327269B (en) | Solid lipidosome preparation of compound cefaclor medicinal composition | |
| CN102626388B (en) | Liposome solid preparation of ozagrel | |
| CN102327217B (en) | Solid cefpodoxime proxetil liposome preparation | |
| CN102440958B (en) | Ibuprofen sodium liposome solid preparation and preparation method thereof | |
| CN102302452B (en) | Pitavastatin calcium lipid solid preparation | |
| CN102327218B (en) | Cefdinir liposome solid preparation | |
| CN102697765A (en) | Ranitidine hydrochloride/bismuth potassium citrate pharmaceutical composition solid lipid nanoparticles preparation | |
| CN103040777B (en) | Olmesartan ester liposome solid preparation | |
| CN102579345B (en) | Irbesartan liposome solid preparation | |
| CN102078299B (en) | Citicoline sodium liposome solid preparation | |
| CN102626395B (en) | Solid preparation of aliskiren-valsartan pharmaceutical composition liposome | |
| CN102366407B (en) | Clindamycin palmitate hydrochloride liposome solid preparation | |
| CN102626391B (en) | Aliskiren-hydrochlorothiazide drug combination liposome solid preparation | |
| CN102406608B (en) | Nisoldipine liposome solid preparation | |
| CN102579344A (en) | Losartan potassium liposome solid preparation | |
| CN103040743A (en) | Solid preparation of telbivudine liposome | |
| CN102266289B (en) | Cilnidipine liposome solid preparation |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C41 | Transfer of patent application or patent right or utility model | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20130814 Address after: 570216 Hainan Province, Haikou city Jinpan Industrial Development Zone Industrial Village No. 3-6 building Patentee after: Hainan Lingkang Pharmaceutical Co., Ltd. Address before: 570216 No. 8 workshop, Haikou Free Trade Zone, Hainan Patentee before: Hainan Lingkang Pharmaceutical Co., Ltd. |
|
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20130123 Termination date: 20161129 |