CN101874779A - Fructose diphosphate sodium liposome solid preparation and novel application thereof - Google Patents
Fructose diphosphate sodium liposome solid preparation and novel application thereof Download PDFInfo
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- CN101874779A CN101874779A CN 200910230610 CN200910230610A CN101874779A CN 101874779 A CN101874779 A CN 101874779A CN 200910230610 CN200910230610 CN 200910230610 CN 200910230610 A CN200910230610 A CN 200910230610A CN 101874779 A CN101874779 A CN 101874779A
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- fructose diphosphate
- diphosphate sodium
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Abstract
The invention provides a fructose diphosphate sodium liposome solid preparation and a novel application thereof. The fructose diphosphate sodium liposome solid preparation is prepared from fructose diphosphate sodium liposome and auxiliary materials, wherein the fructose diphosphate sodium liposome is prepared from fructose diphosphate sodium, lecithin, cholesterol and polyglycerin ester. The invention also provides the application of the fructose diphosphate sodium liposome solid preparation in improving the immunity of tumor patients undergoing chemotherapy. The fructose diphosphate sodium liposome can be prepared by adopting a thin-film dispersion technology to combine a certain amount of the lecithin, the cholesterol, the polyglycerin ester and the active component fructose diphosphate sodium, and is mixed with a certain amount of the auxiliary materials to prepare various solid preparations, so the invention can well solve the problems of poor in-vivo absorption degree and low curative effect, and obtains satisfactory technical effect.
Description
Technical field
The present invention relates to a kind of fructose diphosphate sodium liposome and preparation method thereof, the application of particularly a kind of fructose diphosphate sodium liposome solid preparation and preparation method thereof, and described solid preparation in improving the chemotherapy of tumors patient immune function.
Background technology
Incidence rate and the case fatality rate of malignant tumor in the old people is higher, and in a single day many patients find malignant tumor, has lost the chance of operative treatment, and single radiotherapy or chemotherapy can not obtain satisfied curative effect in clinical practice.Gerontal patient's immunologic function is generally low in addition, and immunotherapy and chemotherapy combined are used, and can alleviate the inhibition of chemotherapy to immunologic function, increases toleration, the raising curative effect of patient to chemotherapy, prolongs life cycle, reduces recurrence.
Fructose Diphosphate sodium is the biochemical product of biologically active, is analeptic and nutrient that scientific and technological circle generally acknowledge.It is the biochemical activity material in human tissue cell's carbohydrate metabolism energy metabolism.In its molecular structure, two high-energy biological phosphate bonds are arranged, bio-energy can be provided effectively, promote the metabolic activity of biological tissue, can strengthen the functional activity of each histoorgan effectively, help the repair cell damage.Simultaneously, it also can play very important effect in the coenzyme of multiple biologically active synthetic.It can regulate the activity of plurality of enzymes system in the glucose metabolism.The activity of exogenous Fructose Diphosphate sodium energy activating phosphatase fructokinase and pyruvate kinase; the concentration of ATP in the cell is increased; promote the interior stream of calcium ion; help the utilization of cellular energy metabolism and glucose under the ischemic anoxia state, thereby the cell on the shield and organ are played protection and recover.
At present, it has application more widely on medicine, health food and beautification product.It can be used as the medicine that recovers and improve the molecular level of cellular metabolism, it is the first aid good medicine of diseases such as acute myocardial infarction, myocarditis, coronary heart disease, myocardial ischemia outbreak, shock, also is ischemic cerebral vascular accident, hepatic disease and all kinds of operating important ancillary drug.For old, ill convalescent period, resisting fatigue positive curative effect is arranged all.
Fructose Diphosphate sodium also has the effect of regulating some enzymatic activitys in the body metabolism; it can effectively strengthen the ability of phagocyte vigor; strengthen antiinflammatory and antineoplastic function; it can promote carbohydrate metabolism to strengthen the oxygen release function of cell, and the toughness of protection cell prevents the decomposition of liver glycogen; quicken the reparation of damaging cells; recover and improve the function of human body cardiac muscle, liver, brain, kidney, so its curative effect body-building function very widely causes the attention of scientific and technological circle day by day.
Patent documentation CN101190187A discloses a kind of fructose diphosphate sodium particle and preparation method, is formed by Fructose Diphosphate sodium and pharmaceutic adjuvant prepared routinely; Patent documentation CN1650871A discloses a kind of sodium fructose diphosphate granule agent and preparation method thereof equally, and this granule contains Fructose Diphosphate sodium, diluent, suspending agent, adopts common process to be prepared from; Patent documentation CN1883489A has invented a kind of dispersible tablet of fructose diphosphate sodium and preparation method thereof, forms by acceptable auxiliary on Fructose Diphosphate sodium, correctives compositions and other pharmaceutics, and dry granulation, pressed powder makes.Above-mentioned patent all is ordinary preparations of Fructose Diphosphate sodium, and trap is relatively poor in its body, can not give play to due drug effect fully and be worth, and has reduced curative effect.
The inventor is through long-term conscientious research, beyond thought discovery is applied to contain a kind of novel form liposome of targeting drug delivery system in the solid preparation of Fructose Diphosphate sodium, not only solved the problem of trap difference in the Fructose Diphosphate sodium body, also can improve chemotherapy of tumors patient's immunologic function, thereby finish the present invention.
Summary of the invention
The object of the present invention is to provide a kind of fructose diphosphate sodium liposome solid preparation, specifically, the combination of lecithin class, cholesterol, polyglycerin ester and active component Fructose Diphosphate sodium by certain content, adopt the thin film dispersion technology to make fructose diphosphate sodium liposome, and then and certain adjuvant be mixed and made into various solid preparations, solve the problem that trap is poor, curative effect is low in the body well, obtained gratifying technique effect.
The technical scheme that the present invention solves is as follows:
The invention provides a kind of Fructose Diphosphate sodium solid preparation, make by fructose diphosphate sodium liposome and adjuvant, wherein said adjuvant is selected from disintegrating agent, filler, binding agent, lubricant, the correctives one or more, it is characterized in that wherein said fructose diphosphate sodium liposome is to be made by the component of following parts by weight:
1 part of Fructose Diphosphate sodium
1.5～14 parts of lecithin classes
0.2～8 part in cholesterol
0.1～10 part of polyglycerin ester.
Preferably, above-mentioned described Fructose Diphosphate sodium solid preparation is characterized in that described fructose diphosphate sodium liposome is to be made by the component of following parts by weight:
1 part of Fructose Diphosphate sodium
1.8～5 parts of lecithin classes
0.5～4 part in cholesterol
0.2～2 part of polyglycerin ester.
Wherein, described lecithin class, can be selected from Ovum Gallus domesticus Flavus lecithin, soybean lecithin, two stearic acid lecithin, two palmitic acid lecithin, two myristic acid lecithin, hydrogenated yolk lecithin and the hydrogenated soy phosphatidyl choline one or more, preferably soya lecithin.
The above-mentioned described Fructose Diphosphate sodium solid preparation of the present invention, it is characterized in that it is 5.5～6.5 pharmaceutically acceptable buffer salt solution that described fructose diphosphate sodium liposome also comprises pH value, for example buffer salt solution is selected from one or more in phosphate buffer, citrate buffer, carbonate buffer solution, borate buffer solution, the acetate buffer.
Preferably, the above-mentioned described Fructose Diphosphate sodium solid preparation of the present invention, it is characterized in that described fructose diphosphate sodium liposome is by comprising that to be prepared as follows step made: (1) is dissolved in lecithin class, cholesterol, polyglycerin ester in the organic solvent, mix homogeneously, organic solvent is removed in decompression on rotary film evaporator, makes immobilized artificial membrane; (2) add buffer salt solution, jolting is stirred and is made the complete aquation of immobilized artificial membrane, and reuse tissue mashing machine spares matter emulsifying, and filtering with microporous membrane makes the blank liposome suspension; (3) Fructose Diphosphate sodium is water-soluble, filtering with microporous membrane, filtrate joins in the blank liposome suspension, is incubated 55-65 ℃ and stirs 30-60 minute, gets fructose diphosphate sodium liposome solution; (4) with above-mentioned solution lyophilization or spray drying, promptly get fructose diphosphate sodium liposome.
Fructose Diphosphate sodium solid preparation of the present invention can be granule, tablet, dispersible tablet or capsule.
The above-mentioned described Fructose Diphosphate sodium solid preparation of the present invention preferably, is to be made by following component by weight: 1 part of fructose diphosphate sodium liposome, 0.2～5 part of filler, 0.05～1 part of disintegrating agent, 0.01～0.2 part of binding agent, 0～3 part of correctives, 0.01～0.05 part of lubricant.
Wherein: described filler is selected from one or more in microcrystalline Cellulose, lactose, starch, pregelatinized Starch, sorbitol, mannitol, dextrin, calcium sulfate, the calcium hydrogen phosphate; Perhaps
Described disintegrating agent is selected from one or more in carboxymethylstach sodium, low-substituted hydroxypropyl cellulose, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, the dried starch; Perhaps
Described binding agent is selected from one or more in 30 POVIDONE K 30 BP/USP 30, hypromellose, starch slurry, sodium carboxymethyl cellulose, the syrup; Perhaps
Described correctives is selected from one or more in sucrose, Aspartane, saccharin sodium, the steviosin; Perhaps
Described lubricant is selected from one or more in magnesium stearate, Pulvis Talci, colloidality silicon dioxide, PEG6000, the sodium lauryl sulphate etc.
As another goal of the invention of the present invention, a kind of preparation method of above-mentioned described Fructose Diphosphate sodium solid preparation also is provided, it comprises the steps: (1) with the fructose diphosphate sodium liposome pulverizing, 80 mesh sieves are standby excessively; (2) filler, disintegrating agent and/or correctives are pulverized, crossed 80 mesh sieves, mix, standby; (3) with above-mentioned supplementary material mix homogeneously, add binding agent system soft material, the granulation of sieving, oven dry, the adding mix lubricant is even, granulate; (4) dried granules is carried out packing or tabletting, make the Fructose Diphosphate sodium solid preparation.
The invention provides a kind of fructose diphosphate sodium liposome, make, and calculate component by weight and be by Fructose Diphosphate sodium, lecithin class, cholesterol and polyglycerin ester:
1 part of Fructose Diphosphate sodium
1.5～14 parts of lecithin classes
0.2～8 part in cholesterol
0.1～10 part of polyglycerin ester.
As the present invention's one preferred embodiment, above-mentioned described fructose diphosphate sodium liposome, calculate component by weight and be:
1 part of Fructose Diphosphate sodium
1.8～5 parts of lecithin classes
0.5～4 part in cholesterol
0.2～2 part of polyglycerin ester.
Wherein, it is 5.5～6.5 pharmaceutically acceptable buffer salt solution that above-mentioned described component also comprises pH value, for example buffer salt solution is selected from one or more in phosphate buffer, citrate buffer, carbonate buffer solution, borate buffer solution, the acetate buffer, the amount of buffer is minimum requirements with hydrated phospholipid film fully, is generally 0.6-0.8 times of volume of consumption of organic solvent.
Above-mentioned described lecithin class can be selected from one or more in Ovum Gallus domesticus Flavus lecithin, soybean lecithin, two stearic acid lecithin, two palmitic acid lecithin, two myristic acid lecithin, hydrogenated yolk lecithin and the hydrogenated soy phosphatidyl choline, preferably soya lecithin.
Further, above-mentioned described fructose diphosphate sodium liposome comprises and is prepared as follows step:
(1) lecithin class, cholesterol, polyglycerin ester are dissolved in the organic solvent, mix homogeneously, organic solvent is removed in decompression on rotary film evaporator, makes immobilized artificial membrane;
(2) add buffer salt solution, jolting is stirred and is made the complete aquation of immobilized artificial membrane, and reuse tissue mashing machine spares matter emulsifying, and filtering with microporous membrane makes the blank liposome suspension;
(3) Fructose Diphosphate sodium is water-soluble, filtering with microporous membrane, filtrate joins in the blank liposome suspension, is incubated 55-65 ℃ and stirs 30-60 minute, gets fructose diphosphate sodium liposome solution;
(4) with above-mentioned solution lyophilization or spray drying, promptly get fructose diphosphate sodium liposome.
In the preparation method of the invention described above liposome, organic solvent can be selected from one or more in chloroform, dichloromethane, ethanol, methanol, the tert-butyl alcohol, n-butyl alcohol, isopropyl alcohol, acetone, ether, benzyl alcohol, the normal hexane, preferred alcohol and isopropyl alcohol.The amount of organic solvent is selected according to the amount of the phospholipid, cholesterol and the polyglycerin ester that add, to dissolve the requirement that mentioned component is a minimum flow fully, preferably based on 1 of phospholipid, cholesterol and polyglycerin ester three gross weight meter: the organic solvent of 3-6 (g/ml) volume.
In the preparation method of the invention described above liposome, the amount of dissolving Fructose Diphosphate sodium water gets final product for Fructose Diphosphate sodium is dissolved fully, preferably from the water based on Fructose Diphosphate sodium weight meter 1: 4-8 (g/ml) volume.
In the preparation method of the invention described above liposome, in the step (2), mixing time is 20-40 minute, can make the complete aquation of immobilized artificial membrane, the rotating speed 200-600r/min of stirring; At a high speed even matter emulsifying can be adopted rotating speed 12000-15000r/min the high-speed stirred 10-20 of tissue mashing machine minute; The available aperture of microporous filter membrane is 0.45 μ m.
As preferably, the preparation of fructose diphosphate sodium liposome of the present invention comprises the steps:
(1) soybean lecithin, cholesterol, polyglycerin ester are dissolved in the organic solvent based on 1 of three's gross weight meter: 3-6 (g/ml) volume, mix homogeneously, organic solvent is removed in decompression on rotary film evaporator, makes immobilized artificial membrane;
(2) buffer salt solution of adding pH value 5.5-6.5, jolting, stir 20-40min, rotating speed 200-600r/min, make the complete aquation of immobilized artificial membrane, reuse tissue mashing machine spares matter emulsifying 10-20min, rotating speed 12000-15000r/min, reuse 0.45 μ m filtering with microporous membrane makes the blank liposome suspension;
(3) Fructose Diphosphate sodium is dissolved in the water based on Fructose Diphosphate sodium weight meter 1: 4-8 (g/ml) volume, 0.45 μ m filtering with microporous membrane, filtrate joins in the blank liposome suspension, is incubated 55-65 ℃ and stirs 30-60min, gets fructose diphosphate sodium liposome solution;
(4) with above-mentioned solution lyophilization or spray drying, promptly get fructose diphosphate sodium liposome.
The present invention also provides the application of Fructose Diphosphate sodium solid preparation in improving the chemotherapy of tumors patient immune function.
The present invention is by specific adjuvant and preferred supplementary material proportioning, make fructose diphosphate sodium liposome, fructose diphosphate sodium liposome provided by the invention and Fructose Diphosphate sodium solid preparation, compared with prior art, have beyond thought effect, major advantage is as follows:
(1) Fructose Diphosphate sodium is wrapped in the liposome, and release is slowly long-acting, has improved its absorption in vivo degree greatly, has solved the problem that the ordinary preparation trap is poor, curative effect is low;
(2) used phospholipid, cholesterol, polyglycerin ester degradation in vivo, avirulence and non-immunogenicity, and can improve the Drug therapy index, reduce drug toxicity and reduce drug side effect;
(3) production technology is simple, and cost is low, can industrial-scale production.
Fructose diphosphate sodium liposome solid preparation provided by the invention carries out stability test and investigates, and accelerated test is 6 months under 40 ℃ of high temperature, relative humidity 75% ± 5% condition, and every detection index does not have significant change.
Fructose diphosphate sodium liposome solid preparation provided by the invention carries out acute toxicity test, abnormal toxicity test and heat source check, and is all up to specification, and safety obtains proof.
The specific embodiment
Further specify the present invention by the following examples, but should not be construed as limitation of the present invention.
Embodiment 1
The preparation of fructose diphosphate sodium liposome
Prescription: Fructose Diphosphate sodium 250g
Soybean lecithin 450g
Cholesterol 125g
Polyglycerin ester 50g
Preparation technology
(1) 450g soybean lecithin, 125g cholesterol, 50g polyglycerin ester are dissolved in the 2000ml ethanol, mix homogeneously, ethanol is removed in decompression on rotary film evaporator, makes immobilized artificial membrane;
(2) add pH value 5.5 sodium dihydrogen phosphate-disodium hydrogen phosphate buffer solution 1200ml, jolting, stir 20min, rotating speed 600r/min, make the complete aquation of immobilized artificial membrane, reuse tissue mashing machine spares matter emulsifying 10min, rotating speed 15000r/min, reuse 0.45 μ m filtering with microporous membrane makes the blank liposome suspension;
(3) the 250g Fructose Diphosphate sodium is dissolved in the 1000ml water, with 0.45 μ m filtering with microporous membrane, filtrate joins in the blank liposome suspension, is incubated 65 ℃ and stirs 30 minutes, gets fructose diphosphate sodium liposome solution;
(4) with above-mentioned solution lyophilization, promptly get fructose diphosphate sodium liposome.
Comparative Examples 1
The preparation of fructose diphosphate sodium liposome
Prescription: Fructose Diphosphate sodium 250g
Two stearic acid lecithin 350g
Cholesterol 45g
NaGC 20g
Preparation technology chooses the outer weight portion of component preferable range of the present invention and forms with embodiment 1, makes fructose diphosphate sodium liposome.
Embodiment 2
The preparation of fructose diphosphate sodium liposome
Prescription: Fructose Diphosphate sodium 250g
Soybean lecithin 1250g
Cholesterol 1000g
Polyglycerin ester 500g
Preparation technology
(1) 1250g soybean lecithin, 1000g cholesterol, 500g polyglycerin ester are dissolved in the 16000ml isopropyl alcohol, mix homogeneously, isopropyl alcohol is removed in decompression on rotary film evaporator, makes immobilized artificial membrane;
(2) citric acid-sodium citrate buffer solution 12000ml of adding pH value 6.5, jolting, stir 40min, rotating speed 200r/min, make the complete aquation of immobilized artificial membrane, reuse tissue mashing machine spares matter emulsifying 20min, rotating speed 12000/min, reuse 0.45 μ m filtering with microporous membrane makes the blank liposome suspension;
(3) the 250g Fructose Diphosphate sodium is dissolved in the water of 2000ml, 0.45 μ m filtering with microporous membrane, filtrate joins in the blank liposome suspension, is incubated 55 ℃ and stirs 60min, gets fructose diphosphate sodium liposome solution;
(4) with above-mentioned solution spray drying, promptly get fructose diphosphate sodium liposome.
Comparative Examples 2
The preparation of fructose diphosphate sodium liposome (preparation technology's difference)
Prescription: Fructose Diphosphate sodium 250g
Soybean lecithin 1250g
Cholesterol 1000g
Polyglycerin ester 500g
Preparation technology
(1) 1250g soybean lecithin, 1000g cholesterol, 500g polyglycerin ester are dissolved in the 16000ml isopropyl alcohol;
(2) the 250g Fructose Diphosphate sodium is dissolved in pH=6.5 citric acid-sodium citrate buffer 10000ml;
(3) with the two mixing, stir, form w/o type Emulsion, the heated and stirred evaporation, when mixture reaches the thickness state, add pH=6.5 citric acid-sodium citrate buffer 2000ml again, continue the heated and stirred evaporation and remove isopropyl alcohol, ultrasonic 15min, be transferred to jolting in the tissue mashing machine, at a high speed even matter emulsifying 20min, rotating speed 12000r/min makes liposome turbid liquor;
(3) with the suspension spray drying, make fructose diphosphate sodium liposome.
Embodiment 3
The preparation of fructose diphosphate sodium particle
Prescription (100)
Fructose diphosphate sodium liposome (in Fructose Diphosphate sodium) 25g
Mannitol 45g
Lactose 30g
Carboxymethylstach sodium 5g
Sucrose 50g
Aspartane 2.5g
30 POVIDONE K 30 BP/USP 30 2.5g
Preparation technology
(1) liposome that contains the 25g Fructose Diphosphate sodium of embodiment 1 preparation is pulverized, crossed 80 mesh sieves, standby;
(2) take by weighing 45g mannitol, 30g lactose, 5g carboxymethylstach sodium, 50g sucrose and 2.5g Aspartane, cross 80 mesh sieves, mix, standby;
(3) with above-mentioned supplementary material mix homogeneously, add 5% 30 POVIDONE K 30 BP/USP
3080% alcoholic solution 50ml makes soft material, and cross 20 mesh sieves and granulate, 60 ℃ of oven dry, 18 mesh sieve granulate get fructose diphosphate sodium particle;
(4) with the dried granules packing, make sodium fructose diphosphate granule agent.
Comparative Examples 3Select the liposome of Comparative Examples 1 preparation for use, make fructose diphosphate sodium particle by embodiment 3 preparation technologies.
Embodiment 4
The preparation of Fructose Diphosphate sodium sheet
Prescription (100)
Fructose diphosphate sodium liposome (in Fructose Diphosphate sodium) 25g
Lactose 6.5g
Carboxymethylstach sodium 2.5g
Hypromellose 0.3g
Magnesium stearate 0.25g
Colloidality silicon dioxide 0.25g
Preparation technology
(1) liposome that contains the 25g Fructose Diphosphate sodium of embodiment 1 preparation is pulverized, crossed 80 mesh sieves, standby;
(2) take by weighing 6.5g lactose, 2.5g carboxymethylstach sodium, cross 80 mesh sieves, mix, standby;
(3) with above-mentioned supplementary material mix homogeneously, add 2% hypromellose, 20% alcoholic solution 15ml system soft material, cross 20 mesh sieves and granulate, 55 ℃ of oven dry, add 0.25g magnesium stearate and 0.25g colloidality silicon dioxide mix homogeneously, 18 mesh sieve granulate get fructose diphosphate sodium particle;
(4), make the Fructose Diphosphate sodium sheet with the dried granules tabletting.
Comparative Examples 4Select the liposome of Comparative Examples 1 preparation for use, make the Fructose Diphosphate sodium sheet by embodiment 4 preparation technologies.
Embodiment 5
The preparation of dispersible tablet of fructose diphosphate sodium
Prescription (100)
Fructose diphosphate sodium liposome (in Fructose Diphosphate sodium) 25g
Starch 3.3
Lactose 3.5g
Carboxymethylstach sodium 2g
Polyvinylpolypyrrolidone 2g
30 POVIDONE K 30 BP/USP 30 1g
Aspartane 0.5g
Magnesium stearate 0.3g
Preparation technology
(1) liposome that contains the 25g Fructose Diphosphate sodium of embodiment 2 preparations is pulverized, crossed 80 mesh sieves, standby;
(2) take by weighing 3.3g starch, 3.5g lactose, 2g carboxymethylstach sodium, 2g polyvinylpolypyrrolidone and 0.5g Aspartane, cross 80 mesh sieves, mix, standby;
(3) with above-mentioned supplementary material mix homogeneously, add 5% 30 POVIDONE K 30 BP/USP
3080% alcoholic solution system soft material is crossed 20 mesh sieves and is granulated, and 55 ℃ of oven dry add 0.3g magnesium stearate mix homogeneously, and 18 mesh sieve granulate get fructose diphosphate sodium particle;
(4) with the dried granules tabletting, make dispersible tablet of fructose diphosphate sodium.
Comparative Examples 5Select the liposome of Comparative Examples 2 preparations for use, make dispersible tablet of fructose diphosphate sodium by embodiment 5 preparation technologies.
Embodiment 6
The capsular preparation of Fructose Diphosphate sodium
Prescription (100)
Fructose diphosphate sodium liposome (in Fructose Diphosphate sodium) 12.5g
Starch 2g
Microcrystalline Cellulose 3g
30 POVIDONE K 30 BP/USP 30 0.6g
Magnesium stearate 0.17g
Preparation technology
(1) liposome that contains the 12.5g Fructose Diphosphate sodium of embodiment 2 preparations is pulverized, crossed 80 mesh sieves, standby;
(2) take by weighing 2g starch, 3g microcrystalline Cellulose, cross 80 mesh sieves, mix, standby;
(3) with above-mentioned supplementary material mix homogeneously, add 3% 30 POVIDONE K 30 BP/USP
3060% alcoholic solution system soft material is crossed 20 mesh sieves and is granulated, and 60 ℃ of oven dry add 0.17g magnesium stearate mix homogeneously, and 18 mesh sieve granulate get fructose diphosphate sodium particle;
(4), make the fructose diphosphate natrium capsule with the dried granules packing.
Comparative Examples 6Select the liposome of Comparative Examples 2 preparations for use, make the fructose diphosphate natrium capsule by embodiment 3 preparation technologies.
Test example 1
The mensuration of envelop rate
Get the liposome of embodiment 1-2 and Comparative Examples 1-2 preparation, the total content that high performance liquid chromatography detects Fructose Diphosphate sodium is M, selects for use column chromatography to separate liposome.
Get 1.5g sephadex G-50, soak more than the swelling 12h with the pH6.8 phosphate buffer, pack in the chromatographic column (200 * 10mm) into, with above-mentioned phosphate buffer flushing balance, getting the fructose diphosphate sodium liposome that embodiment 1-2 and Comparative Examples 1-2 obtain respectively is dissolved in water, make the solution that every 1ml contains the about 18mg of Fructose Diphosphate sodium, get solution 1.6ml respectively and add the chromatographic column top, with phosphate buffer 50ml eluting, flow velocity 1.5ml/min, the eluent of collecting adds rupture of membranes agent (ethanol: 50ml benzyl alcohol=6: 1), mixing, the content M1 of high performance liquid chromatography detection Fructose Diphosphate sodium.
Envelop rate %=M
1/ M * 100%.
Table 1 entrapment efficiency determination result
By above result as can be known, the liposome encapsulation that the present invention makes is very high, meets the actual production requirement substantially; The liposome encapsulation that the Comparative Examples of the Comparative Examples of proportioning and Different Preparation makes and the scope of the invention is write out a prescription outward is very low, has compared tangible gap with embodiment, is not suitable for production requirement.
Test example 2
The detection of particle diameter
Get the liposome of embodiment 1-2 and Comparative Examples 1-2 preparation, adopt micro-image analyzer to measure the particle size distribution of liposome, result such as table 2:
Table 2 particle diameter testing result
By above result as can be known, the liposome that embodiment 1-2 makes shows spherical, ellipticity, and particle diameter is even, and scope is 100-200nm; The liposome shape that Comparative Examples 1-2 makes is indefinite, not of uniform size, and particle diameter is inhomogeneous, and scope is 400-800nm.
Test example 3
Stability test
Get fructose diphosphate sodium liposome preparation and (Shanghai Tianlong Pharmaceutical Co., Ltd.'s production of listing preparation Fructose Diphosphate sodium sheet that embodiment 3-6 and Comparative Examples 3-6 make, lot number 20080904), under 40 ℃ of high temperature, relative humidity 75% ± 5% condition 6 months, carry out accelerated test and investigate, the result is as follows:
Table 3 accelerated test is investigated
By above result as can be known, the sample dissolution of embodiment of the invention 3-6 is all more than 90%, be higher than about 84% of listing tablet far away, illustrate that the fructose diphosphate sodium liposome that the present invention makes has improved its dissolubility, thereby improved degree of absorbing in the body accordingly.After the accelerated test 6 months, significant change does not take place in sample dissolution, content and the related substance of embodiment of the invention 3-6, and the sample of Comparative Examples 3-6 preparation and listing formulation content, dissolution descend bigger, related substance is against regulation, illustrates that the fructose diphosphate sodium liposome that the present invention makes has improved its stability of formulation.
Test example 4
Clinical trial is prepared
1, patient's data
Old malignant tumor patient 45 examples, wherein male 32 examples, women 13 examples, 65～78 years old age, average (72.3 ± 8.4) year, confirm through pathology: pulmonary carcinoma 16 examples, gastric cancer 9 examples, cancer of pancreas 8 examples, intestinal cancer 7 examples, the esophageal carcinoma 2 examples, hepatocarcinoma 3 examples wherein have 15 customary excisions.Above patient is II～IV phase clinical stages.It is 22 examples that above-mentioned patient is divided into matched group according to tumor kind, stadium and following chemotherapy regimen in the random packet mode, and 23 examples are organized in treatment, and two groups relatively have comparability (seeing table 4 for details).
Table 4 liang group malignant tumor and pathological staging (example)
2, medication
Two groups of chemotherapy regimens that the patient adopts: pulmonary carcinoma is gemcitabine (GEM)+DDP, gastric cancer is paclitaxel (Taxol)+5-FU+DDP, and cancer of pancreas is CEM+5-FU, and intestinal cancer is CF+5-FU, the esophageal carcinoma is MMC+DDP+5-FU, and hepatocarcinoma gets involved chemotherapy for the EPI+5-FU Hepatic artery.The treatment group adds the fructose diphosphate natrium capsule 0.65g with the embodiment of the invention 6 preparations, every day 2 times, 4 weeks of logotype simultaneously.All patients do not have the chemotherapy contraindication.
3, observation item
The cellular immune function and the humoral immune function in 4 weeks behind 1 week and the end of chemotherapy before measuring chemotherapy respectively, behind the end of chemotherapy, cellular immune function comprises peripheral blood CD3, CD4, CD8 percentage rate and CD4/CD8, NK cell proportion, and the humoral immune function index comprises serum immunoglobulin IgG, IgM and complement C3, C4.
4, statistical method adopts variance analysis.
Test example 5
Clinical test results
1, cellular immune function changes
1 week, 4 all peripheral blood CD3, CD4, CD4/CD8 and NK cell percentage all before chemotherapy (P＜0.05) after the treatment group chemotherapy.And matched group CD4/CD8 difference does not have significance (P＞0.05), all significantly is lower than the preceding P of chemotherapy＜0.05 after CD3, CD4 percentage rate and the NK cell percentage chemotherapy in 1 week, 4 weeks), see Table 5.
Change before and after the treatment of table 5 cellular immunization index (%, x ± s)
2, humoral immune function changes
Difference does not have significance (P＞0.05) before and after the horizontal chemotherapy of treatment group IgG, and significantly is lower than (P＜0.01) before the chemotherapy after the horizontal chemotherapy of matched group IgG.There are no significant (P＞0.05) for difference before and after treatment group and matched group serum IgM, the horizontal chemotherapy of C3, C4.See Table 6.
Change before and after the treatment of table 6 humoral immunization index (g/L, x ± s)
We have observed Fructose Diphosphate sodium to Immune Effects in the old malignant tumor patient chemotherapy process, find in the application process, significantly be lower than after simple chemotherapy peripheral blood CD3, CD4 and the NK cell percentage chemotherapy (P＜0.05) before the chemotherapy, add with behind the fructose diphosphate sodium liposome capsule, 1 week, 3 all CD3, CD4, CD4/CD8 and NK cell percentage all are significantly higher than (P＜0.05) before the chemotherapy after patient's chemotherapy.Aspect humoral immunization, before significantly being lower than chemotherapy after the simple horizontal chemotherapy of patients undergoing chemotherapy IgG, there are no significant for difference before and after adding usefulness fructose diphosphate sodium liposome Capsules group IgG level, there are no significant (P＞0.05) for difference before and after treatment group and matched group serum IgM, the horizontal chemotherapy of C3, C4, the generation that shows the fructose diphosphate sodium liposome antagonist has facilitation, patients undergoing chemotherapy IgG level is kept normally, and not remarkable to complement level affects such as C3, C4.
Fructose diphosphate sodium liposome solid preparation can significantly improve the homoimmune function that is suppressed by chemotherapy as a kind of immunostimulant and chemotherapy combined application, strengthens the toleration of patient to chemotherapy.This preparation is having gratifying application prospect as a kind of active immunity activator aspect the treatment human tumor.
Claims (10)
1. Fructose Diphosphate sodium solid preparation, make by fructose diphosphate sodium liposome and adjuvant, wherein said adjuvant is selected from disintegrating agent, filler, binding agent, lubricant, the correctives one or more, it is characterized in that wherein said fructose diphosphate sodium liposome is to be made by the component of following parts by weight:
1 part of Fructose Diphosphate sodium
1.5～14 parts of lecithin classes
0.2～8 part in cholesterol
0.1～10 part of polyglycerin ester.
2. Fructose Diphosphate sodium solid preparation according to claim 1 is characterized in that described fructose diphosphate sodium liposome is to be made by the component of following parts by weight:
1 part of Fructose Diphosphate sodium
1.8～5 parts of lecithin classes
0.5～4 part in cholesterol
0.2～2 part of polyglycerin ester.
3. according to the described Fructose Diphosphate sodium solid preparation of claim 1-2, wherein said lecithin class is selected from one or more in Ovum Gallus domesticus Flavus lecithin, soybean lecithin, two stearic acid lecithin, two palmitic acid lecithin, two myristic acid lecithin, hydrogenated yolk lecithin and the hydrogenated soy phosphatidyl choline, preferably soya lecithin.
4. according to the described Fructose Diphosphate sodium solid preparation of claim 1-3, it is characterized in that it is 5.5～6.5 pharmaceutically acceptable buffer salt solution that described fructose diphosphate sodium liposome also comprises pH value, for example buffer salt solution is selected from one or more in phosphate buffer, citrate buffer, carbonate buffer solution, borate buffer solution, the acetate buffer.
5. according to the described Fructose Diphosphate sodium solid preparation of claim 1-4, it is characterized in that described fructose diphosphate sodium liposome is by comprising that to be prepared as follows step made:
(1) lecithin class, cholesterol, polyglycerin ester are dissolved in the organic solvent, mix homogeneously, organic solvent is removed in decompression on rotary film evaporator, makes immobilized artificial membrane;
(2) add buffer salt solution, jolting is stirred and is made the complete aquation of immobilized artificial membrane, and reuse tissue mashing machine spares matter emulsifying, and filtering with microporous membrane makes the blank liposome suspension;
(3) Fructose Diphosphate sodium is water-soluble, filtering with microporous membrane, filtrate joins in the blank liposome suspension, is incubated 55-65 ℃ and stirs 30-60 minute, gets fructose diphosphate sodium liposome solution;
(4) with above-mentioned solution lyophilization or spray drying, promptly get fructose diphosphate sodium liposome.
6. according to the described Fructose Diphosphate sodium solid preparation of claim 1-5, it is granule, tablet, dispersible tablet or capsule.
7. according to the described Fructose Diphosphate sodium solid preparation of claim 1-6, it is characterized in that described solid preparation is to be made by following component by weight: 1 part of fructose diphosphate sodium liposome, 0.2～5 part of filler, 0.05～1 part of disintegrating agent, 0.01～0.2 part of binding agent, 0～3 part of correctives, 0.01～0.05 part of lubricant.
8. according to the described Fructose Diphosphate sodium solid preparation of claim 1-7, wherein: described filler is selected from one or more in microcrystalline Cellulose, lactose, starch, pregelatinized Starch, sorbitol, mannitol, dextrin, calcium sulfate, the calcium hydrogen phosphate; Perhaps described disintegrating agent is selected from one or more in carboxymethylstach sodium, low-substituted hydroxypropyl cellulose, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, the dried starch; Perhaps described binding agent is selected from one or more in 30 POVIDONE K 30 BP/USP 30, hypromellose, starch slurry, sodium carboxymethyl cellulose, the syrup; Perhaps described correctives is selected from one or more in sucrose, Aspartane, saccharin sodium, the steviosin; Perhaps described lubricant is selected from one or more in magnesium stearate, Pulvis Talci, colloidality silicon dioxide, PEG6000, the sodium lauryl sulphate etc.
9. method for preparing the described Fructose Diphosphate sodium solid preparation of claim 1-8, it comprises the steps: that (1) pulverize fructose diphosphate sodium liposome, crosses 80 mesh sieves, and is standby; (2) filler, disintegrating agent and/or correctives are pulverized, crossed 80 mesh sieves, mix, standby; (3) with above-mentioned supplementary material mix homogeneously, add binding agent system soft material, the granulation of sieving, oven dry, the adding mix lubricant is even, granulate; (4) dried granules is carried out packing or tabletting, make the Fructose Diphosphate sodium solid preparation.
10. according to the application of the described Fructose Diphosphate sodium solid preparation of claim 1-9 in preparation raising chemotherapy of tumors patient immune function medicine.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102125569A (en) * | 2011-03-18 | 2011-07-20 | 浙江大学 | Application of 1, 6-bisphosphate fructose in preparation of anti-cancer medicaments |
| CN116270522A (en) * | 2023-04-27 | 2023-06-23 | 北京华靳制药有限公司 | Fructose diphosphate sodium capsule and preparation method thereof |
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| IT1164363B (en) * | 1983-08-03 | 1987-04-08 | Foscama Biomed Chim Farma | THERAPEUTIC PROCEDURE FOR THE USE OF EMBORNED LIPOSOMES FRUCTOSE 1.6 DIPHOSPHATE AND PROCEDURE FOR THE PREPARATION OF THE SAME |
| CN101601655B (en) * | 2009-07-03 | 2011-02-16 | 王明 | Maleic acid cinepazide liposome injection and new application thereof |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102125569A (en) * | 2011-03-18 | 2011-07-20 | 浙江大学 | Application of 1, 6-bisphosphate fructose in preparation of anti-cancer medicaments |
| CN102125569B (en) * | 2011-03-18 | 2012-09-26 | 浙江大学 | Application of 1, 6-bisphosphate fructose in preparation of anti-cancer medicaments |
| CN116270522A (en) * | 2023-04-27 | 2023-06-23 | 北京华靳制药有限公司 | Fructose diphosphate sodium capsule and preparation method thereof |
| CN116270522B (en) * | 2023-04-27 | 2024-04-19 | 北京华靳制药有限公司 | Fructose diphosphate sodium capsule and preparation method thereof |
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