CN101632675A - Ferrous fumarate and folic acid pharmaceutical composition and liposome solid preparation thereof - Google Patents
Ferrous fumarate and folic acid pharmaceutical composition and liposome solid preparation thereof Download PDFInfo
- Publication number
- CN101632675A CN101632675A CN200910017860A CN200910017860A CN101632675A CN 101632675 A CN101632675 A CN 101632675A CN 200910017860 A CN200910017860 A CN 200910017860A CN 200910017860 A CN200910017860 A CN 200910017860A CN 101632675 A CN101632675 A CN 101632675A
- Authority
- CN
- China
- Prior art keywords
- folic acid
- liposome
- ferrous fumarate
- pharmaceutical composition
- acid pharmaceutical
- 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.)
- Pending
Links
Abstract
The invention relates to a ferrous fumarate and folic acid pharmaceutical composition, a liposome solid preparation and a preparation method thereof. The solid preparation contains a liposome of the ferrous fumarate and folic acid pharmaceutical composition, and a pharmaceutically acceptable excipient, and specifically contains 1 part of the liposome of the ferrous fumarate and folic acid pharmaceutical composition, 0.2-1.5 parts of a filling agent, 0.01-0.5 parts of a disintegrant, 0.01-0.2 parts of an adhesive and 0.01-0.3 parts of a lubricant.
Description
Technical field
The present invention relates to a kind of ferrous fumarate and folic acid pharmaceutical composition and lipidosome solid preparation and preparation method thereof of containing, belong to medical technical field.
Background technology
According to WHO report, Asia pregnant woman anemia prevalence is 40%.Domestic data shows that trimester of pregnancy merges the anemia incidence rate and reaches more than 30%.Anemia during pregnancy is the most common with iron deficiency anemia, accounts for 68%.To trimester of pregnancy serum ferritin, folic acid and the content detection data of VitB12 show: the content of serum levels of iron haemproteins, folic acid increases with the pregnancy period and reduces.
Hematinic commonly used is a ferrous sulfate, and ferrous fumarate equally is the ferrous iron preparation with ferrous sulfate, compares with ferrous sulfate, and distinguishing feature is arranged.Ferrous fumarate is orange red color or brown ceramic powder, is slightly soluble in water, promptly is slightly soluble in ethanol, and ferrous fumarate is to absorb at duodenum and barnyard epimere with the ferrous ion form in animal body.The ferrum that absorbs, major part participate in the synthetic of hemoglobin in bone marrow, remainder is stored in the netted chrotoplast of bone marrow, liver and spleen with ferritin and the xanchromatic form of iron content blood, and some is present in the intestinal mucosa cells in addition.The excretion pathway of ferrum mainly is intestinal and skin, in urine and the sweat gland a small amount of discharge is arranged also.It is recycling when most of ferrum discharge after haemoglobin molecule is destroyed.
Folic acid is a kind of b vitamin that extensively is present in the green vegetables, owing to it extracts from plant leaf the earliest and gets, so called after " folic acid ".The chemistry of folic acid is called " pteroylglutamic acid ", is by pteridine acid, para-amino benzoic acid and glutamic acid be combined into.Human (or other animals) are obstructed as lacking some amino acid whose change of folic acid, make the nucleic acid dyssynthesis in the erythrocyte forming process, and erythrocytic growth and anacmesis can cause megaloblastic anemia and leukopenia.Folic acid is even more important to the anemia of pregnant woman, as lacking folic acid in 3 months at conceived, can cause the fetal neural tube developmental defect, split animal brains thereby increase, the incidence rate of anencephaly, secondly, the frequent Supplement of folic acid of anemia of pregnant woman can prevent that neonatal weight from kicking the beam, premature labor and baby's cleft palate congenital malformatioies such as (cleftlips).Research is also found: 1, antitumor action, and 2, the neurocyte and the brain cell development of infant had facilitation, 3, folic acid can be used as schizophrenia patient's auxiliary therapeutical agent, it has significant mitigation to this disease.In addition, folic acid also can be used for treating chronic atrophic gastritis, suppresses the bronchus squamous transforms and control causes because of hyperhomocysteinemiainjury coronary sclerosis, myocardial damage and myocardial infarction etc.
Non-anemia of pregnant woman woman folic acid demand every day is 50～100 μ g, and after the gestation, the folic acid requirement increases, and anemia of pregnant woman's daily requirement amount is 300～400 μ g, and requirement is more during multiple pregnancy.Trimester of pregnancy, Supplement of folic acid was except that being used for the treatment of megaloblastic anemia, can also be used to prevent effects such as fetal neural tube deformity.Ferrous fumarate and folic acid " twin " preparation makes things convenient for the anemia of pregnant woman to use, and can prevent to give birth to defective, and the curative effect of chalybeate is got twice the result with half the effort when improving iron deficiency anemia simultaneously with folic acid deficiency.
The present drug combination preparation of the fixed dosage of forming with two kinds of active component of ferrous fumarate and the folic acid product of not producing and go on the market at home.And multiple commodity listing has abroad been arranged, wherein go on the market in Britain
Sheet (containing ferrous fumarate and folic acid, wherein iron content 100mg, folic acid 350 μ g) is used to prevent anemia of pregnant woman's ferrum and folic acid deficiency, becomes OTC medicine salable, and is recorded by British Pharmacopoeia.
Although domestic early having recognized that clinically replenished chalybeate and the folic acid importance to the prevention anemia in pregnancy simultaneously, except that the ferrous YESUAN PIAN of sulphuric acid, still there is not exploitation to contain the drug combination preparation of the fixed dosage of ferrous fumarate and two kinds of active component of folic acid; Has only Nutrilite on the market as health food
Iron folic acid sheet (containing ferrous fumarate, Ferrous gluconate and folic acid) is sold.
Patent documentation CN101278922A discloses a kind of medicament composition capsule that contains active component ferrous fumarate and folic acid, it claims folic acid, homogeneity and the stability of ferrous fumarate in drug combination preparation that has guaranteed therapeutic dose, and the active ingredient stripping quantity is big, absorb in animal body steadily and to reach the peak fast, improved bioavailability.It should be apparent to those skilled in the art that and recognize; it only is to add ordinary excipients directly to fill afterwards and conventional capsule; do not provide protective measure to folic acid and ferrous fumarate, enter in the body after, can not produce technique effects such as described steady release.
From people such as late 1960s Rahman at first use liposome as pharmaceutical carrier since, continuous progress along with science and technology, liposome preparation technology is progressively perfect, and the liposome mechanism of action is further illustrated, and liposome becomes the hot technology field of current research.Verified, liposome is fit to vivo degradation, avirulence and non-immunogenicity, and the what is more important liposome can improve the Drug therapy index, reduces drug toxicity and reduce drug side effect as pharmaceutical carrier.The inventor imagines thus with liposome folic acid and ferrous fumarate, obtains the expectation pharmacological activity, obtains to discharge stably.
Summary of the invention
The present invention develops the Liposomal formulation of ferrous fumarate and folic acid pharmaceutical composition, makes things convenient for clinical application, effectively prevents anemia of pregnant woman's trimester of pregnancy ferrum and folic acid deficiency.
The object of the present invention is to provide a kind of solid preparation of ferrous fumarate and folic acid pharmaceutical composition, specifically, the combination of hydrogenated soy phosphatidyl choline, cholesterol, polyglycerin ester, poloxamer 188 and active component ferrous fumarate and folic acid by certain content, adopt the thin film dispersion technology to make the liposome of ferrous fumarate and folic acid pharmaceutical composition, and then make tablet with certain mixed with excipients.
The liposome that the purpose of this invention is to provide a kind of ferrous fumarate and folic acid pharmaceutical composition comprises the component of weight portion meter: 1883.5～120 parts of ferrous fumarate 12-36 part, folic acid 0.01-0.7 part, hydrogenated soy phosphatidyl choline 20-150 part, cholesterol 5-100 part, polyglycerin ester 3-90 part and poloxamers.
As the present invention's one preferred embodiment, the liposome of above-mentioned ferrous fumarate and folic acid pharmaceutical composition comprises components by weight portions: 18830 parts of 22 parts of ferrous fumarate, 0.35 part in folic acid, 50 parts of hydrogenated soy phosphatidyl cholines, 13 parts in cholesterol, 18 parts of polyglycerin ester and poloxamers.
As preferably, the liposome of above-mentioned ferrous fumarate and folic acid pharmaceutical composition is characterized in that making by the method that comprises following steps:
(1) hydrogenated soy phosphatidyl choline, cholesterol, polyglycerin ester and poloxamer 188 are dissolved in the solvent, mix homogeneously, removing desolvates makes immobilized artificial membrane;
(2) add the buffer salt solution stirring and make the complete aquation of immobilized artificial membrane, make the blank liposome suspension;
(3) ferrous fumarate and folic acid are dispersed in the water, add in the blank liposome suspension, make liposome turbid liquor;
(4), promptly get the liposome of ferrous fumarate and folic acid pharmaceutical composition with suspension lyophilization or spray drying.
Wherein, described buffer salt solution, be preferably the pharmaceutically acceptable buffer salt solution of pH value 4.5～5.5, 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 described buffer salt solution of preferred adding is counted 300～100 weight portions based on above weight portion.
Wherein, described solvent is an organic solvent, for example is selected from ethanol, methanol, the tert-butyl alcohol, n-butyl alcohol, isopropyl alcohol, acetone, ether, benzyl alcohol, the normal hexane one or more, and preferred solvent is a n-butyl alcohol.
Polyglyceryl fatty acid ester (PGE) is to be made by fatty acid and polyglycereol reaction, is called for short polyglycerin ester.The high-grade aliphatic ester of polyglycereol is the non-ionic surface active agent of function admirable, since its hydrophilic with the increase of glycerol polymerization degree increase, lipophile is different with the difference of fatty acid alkyl, so change the kind of glycerol polymerization degree and fatty acid can obtain hydrophile-lipophile balance value (HLB value) by the different performance of 1-16-series non-ionic surfactants to be to be applicable to various special purposes.(the HLB value) of polyglycerin ester of the present invention is preferably 12.
As preferably, the liposome of above-mentioned ferrous fumarate and folic acid pharmaceutical composition adds buffer salt solution and stirs and make the complete aquation of immobilized artificial membrane in the preferred steps (2), and reuse tissue mashing machine spare matter emulsifying, the one-tenth liposome turbid liquor; Perhaps, wherein in the step (3) ferrous fumarate and folic acid are dispersed in the water, add in the blank liposome suspension, be incubated 55-65 ℃, reuse tissue mashing machine spares matter emulsifying 10-30min, gets liposome turbid liquor.
Further, as one of most preferred embodiment of the present invention, the liposome of above-mentioned ferrous fumarate and folic acid pharmaceutical composition is to make by the method that comprises the steps:
(1) hydrogenated soy phosphatidyl choline, cholesterol, polyglycerin ester and poloxamer 188 are dissolved in the n-butyl alcohol, mix homogeneously, n-butyl alcohol is removed in decompression on rotary film evaporator, makes immobilized artificial membrane;
(2) add the buffer salt solution stirring and make the complete aquation of immobilized artificial membrane,, make the blank liposome suspension with the even matter emulsifying of tissue mashing machine;
(3) ferrous fumarate and folic acid are dispersed in the water, add in the blank liposome suspension, be incubated 55-65 ℃, reuse tissue mashing machine spares matter emulsifying 10-30min, gets the liposome turbid liquor of ferrous fumarate and folic acid pharmaceutical composition;
(4), promptly get the ferrous fumarate and folic acid pharmaceutical composition liposome with suspension lyophilization or spray drying.
As another goal of the invention of the present invention, a kind of solid preparation that contains the liposome of ferrous fumarate and folic acid pharmaceutical composition also is provided, it is characterized in that comprising the liposome and the pharmaceutically acceptable excipient composition of above-mentioned ferrous fumarate and folic acid pharmaceutical composition; Described solid preparation is the following component that preferably comprises by weight: 1 part of the liposome of ferrous fumarate and folic acid pharmaceutical composition, 0.2～1.5 part of filler, 0.01～0.5 part of disintegrating agent, 0.01～0.2 part of binding agent, 0.01～0.3 part of lubricant.
The above filler, disintegrating agent, binding agent, lubricant are selected from this area excipient commonly used.Those skilled in the art it is also understood that can add other pharmaceutically acceptable excipient according to actual needs makes required tablet.
Wherein:
Described filler is one or more in starch, microcrystalline Cellulose, lactose, pregelatinized Starch, sorbitol, mannitol, dextrin, calcium sulfate, calcium hydrogen phosphate preferably;
Described disintegrating agent is one or more in carboxymethylstach sodium, low-substituted hydroxypropyl cellulose, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose preferably;
Described binding agent is one or more in polyvidone K30, hypromellose, starch slurry, sodium carboxymethyl cellulose preferably;
Described lubricant is one or more in magnesium stearate, Pulvis Talci, colloidality silicon dioxide, PEG6000, sodium lauryl sulphate etc. preferably.
Further, the preparation method of the solid preparation of the described liposome that contains ferrous fumarate and folic acid pharmaceutical composition comprises the steps:
(1) liposome of ferrous fumarate and folic acid pharmaceutical composition is pulverized (liposomal encapsulated back particle diameter is very little, pulverizes and can not destroy), crossed 80 mesh sieves, standby;
(2) filler, disintegrating agent 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), make the tablet of ferrous fumarate and folic acid with the dried granules tabletting.
The present invention also aims to provide the application of liposome in the medicine of preparation treatment anemia of ferrous fumarate and folic acid pharmaceutical composition.
The present invention makes the liposome of ferrous fumarate and folic acid pharmaceutical composition by suitable supplementary material and proportioning thereof, makes the solid preparation of ferrous fumarate and folic acid pharmaceutical composition again with conventional excipients pharmaceutically.The liposome of ferrous fumarate and folic acid pharmaceutical composition provided by the invention and the solid preparation of ferrous fumarate and folic acid pharmaceutical composition mainly contain following advantage:
(1) folic acid is embedded in the liposome, has solved the problem of stable difference, has improved drug effect and bioavailability, has guaranteed product quality;
(2) ferrous fumarate is embedded in the liposome, and ferrous ion is stable, is difficult to be oxidized to ferric iron, and ferrum amount height, and the content of ferrum is 33% in the ferrous fumarate;
(3) used hydrogenated soy phosphatidyl choline, cholesterol, poloxamer 188 and polyglycerin ester degradation in vivo, avirulence and non-immunogenicity, and can improve the Drug therapy index, reduce drug toxicity and reduce drug side effect;
(4) production technology is simple, and cost is low, can industrial-scale production;
The preparation technology of liposome is ripe already, prior art also discloses multiple preparation technology, for example CN101391098A discloses a kind of melittin Liposomal formulation, it is characterized in that being made up of 1 part of melittin, soybean phospholipid 5-40 part, cholesterol 1.3-10 part, poloxamer 10-140 part.CN1813678A discloses a kind of Hepatitis B virus vaccine liposome, and wherein phospholipid can be selected from lecithin, cephalin, soybean phospholipid, hydrogenated phospholipid; Ionic surfactant is selected from sodium cholate, sodium deoxycholate, or nonionic surfactant is selected from spans, Tweens, poloxamer.Application 200710175540.3 discloses a kind of preparation method of liposome, it is characterized in that this method is: get injection soybean phospholipid 300-500 weight portion, cholesterol 80-150 weight portion and be dissolved in the 10-40 parts by volume ether, sinomenine hydrochloride 30-70 weight portion is dissolved in the 5-20 parts by volume pH7.1-7.5 phosphate buffer that contains 30-70 weight portion sodium cholate as water as organic facies; Under stirring water is dropwise added in the organic facies, wait to dropwise and continue to stir 10-30 minute, obtain water/oil type emulsion; Rotary evaporation eliminates ether; Continue under the room temperature to stir and promptly got drug-loaded liposome in 20-40 minute.The embodiment 1 of application 200810155948.9 discloses the liposome of paclitaxel, comprises: paclitaxel 1g, soybean phospholipid 30g, Tween 80 1g, sodium deoxycholate 1g, cholesterol 3g, mannitol 60g, water 600mL.
Those skilled in the art should fully understand, though the preparation technology of liposome generally obtains, but each composition classification of formation liposome and the selection of content and non-obvious thereof, the applicant need pay the liposome with excellent encapsulation rate that performing creative labour just can obtain the certain ingredients proportioning.Following examples will prove creative place of the present invention one by one.
The solid preparation of ferrous fumarate and folic acid pharmaceutical composition 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.
The solid preparation of ferrous fumarate and folic acid pharmaceutical composition 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.
The preparation of the liposome of embodiment 1 ferrous fumarate and folic acid pharmaceutical composition
Prescription:
Ferrous fumarate 22g
Folic acid 0.35g
Hydrogenated soy phosphatidyl choline 50g
Cholesterol 13g
Polyglycerin ester 18g
Poloxamer 188 30g
Preparation technology
(1) 50g hydrogenated soy phosphatidyl choline, 13g cholesterol, 18g polyglycerin ester and 30g poloxamer 188 are dissolved in the 1000ml n-butyl alcohol, mix homogeneously, n-butyl alcohol is removed in decompression on rotary film evaporator, makes immobilized artificial membrane;
(2) phosphoric acid-sodium dihydrogen phosphate buffer 500ml of adding pH=4.5 stirs and makes the complete aquation of immobilized artificial membrane, and reuse tissue mashing machine spares matter emulsifying 20min, and rotating speed 13000r/min makes the blank liposome suspension; (wherein, the 22g ferrous fumarate is 22 parts, and buffer solution 500ml is that 500g is 500 parts)
(3) 22g ferrous fumarate and 0.35g folic acid are dispersed among the water 300ml, add in the blank liposome suspension, be incubated 60 ℃, reuse tissue mashing machine spares matter emulsifying 30min, gets the liposome turbid liquor of ferrous fumarate and folic acid pharmaceutical composition;
(4), promptly get the liposome of ferrous fumarate and folic acid pharmaceutical composition with the suspension lyophilization.
Comparative Examples 1
The preparation of the liposome of ferrous fumarate folic acid pharmaceutical composition
Prescription:
Ferrous fumarate 22g
Folic acid 0.35g
Hydrogenated soy phosphatidyl choline 50g
Cholesterol 13g
Poloxamer 188 30g
Preparation technology chooses the combination of non-preferred ingredient of the present invention with embodiment 1, makes the liposome of ferrous fumarate and folic acid pharmaceutical composition.
The preparation of the liposome of Comparative Examples 2 ferrous fumarate and folic acid pharmaceutical compositions
Prescription:
Ferrous fumarate 22g
Folic acid 0.35g
Hydrogenated soy phosphatidyl choline 50g
Cholesterol 13g
Polyglycerin ester 18g
Preparation technology chooses the combination of non-preferred ingredient of the present invention with embodiment 1, makes the liposome of ferrous fumarate and folic acid pharmaceutical composition.
Embodiment 2
The preparation of the liposome of ferrous fumarate and folic acid pharmaceutical composition
Prescription:
Ferrous fumarate 22g
Folic acid 0.35g
Hydrogenated soy phosphatidyl choline 80g
Cholesterol 20g
Polyglycerin ester 12g
Poloxamer 188 44g
Preparation technology
(1) 80g hydrogenated soy phosphatidyl choline, 20g cholesterol, 12g polyglycerin ester and 44g poloxamer 188 are dissolved in the 1500ml n-butyl alcohol, mix homogeneously, n-butyl alcohol is removed in decompression on rotary film evaporator, makes immobilized artificial membrane;
(2) citric acid-sodium citrate buffer solution 800ml of adding pH=5.5 stirs and makes the complete aquation of immobilized artificial membrane, and reuse tissue mashing machine spares matter emulsifying 15min, and rotating speed 15000r/min makes the blank liposome suspension;
(3) 22g ferrous fumarate and 0.35g folic acid are dispersed among the water 300ml, add in the blank liposome suspension, be incubated 55 ℃, reuse tissue mashing machine spares matter emulsifying 20min, gets the liposome turbid liquor of ferrous fumarate and folic acid pharmaceutical composition;
(4), promptly get the liposome of ferrous fumarate and folic acid pharmaceutical composition with the suspension spray drying.
Embodiment 3
The preparation of the tablet of ferrous fumarate and folic acid pharmaceutical composition
Select the ferrous fumarate and folic acid medicine 22.35g (containing ferrous fumarate 22g, the liposome 0.35g of folate composition) of embodiment 1 for use
Starch 52g
Lactose 46g
Carboxymethylstach sodium 8g
30 POVIDONE K 30 BP/USP 30 2.5g
Magnesium stearate 1.5g
Preparation technology
(1) liposome that contains the 22.35g ferrous fumarate and folic acid pharmaceutical composition of embodiment 1 preparation is pulverized, crossed 80 mesh sieves, standby;
(2) take by weighing 52g starch, 46g lactose, carboxymethylstach sodium 8g, 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 system soft material, cross 20 mesh sieves and granulate 60 ℃ of oven dry, 18 mesh sieve granulate;
(4), make the tablet of ferrous fumarate and folic acid pharmaceutical composition with the dried granules tabletting.
Comparative Examples 3
The preparation of the tablet of ferrous fumarate and folic acid pharmaceutical composition
Select the ferrous fumarate and folic acid medicine 22.35g (containing ferrous fumarate 22g, the liposome 0.35g of folate composition) of Comparative Examples 1 for use
Starch 52g
Lactose 46g
Carboxymethylstach sodium 8g
30 POVIDONE K 30 BP/USP 30 2.5g
Magnesium stearate 1.5g
Preparation technology is with embodiment 3, and the liposome that adopts Comparative Examples 1 preparation makes the tablet of ferrous fumarate and folic acid pharmaceutical composition as active component.
Embodiment 4
The preparation of the tablet of ferrous fumarate and folic acid pharmaceutical composition
Select the ferrous fumarate and folic acid medicine 22.35g (containing ferrous fumarate 22g, the liposome 0.35g of folate composition) of embodiment 2 for use
Microcrystalline Cellulose 44g
Lactose 60g
Low-substituted hydroxypropyl cellulose 6g
Hypromellose 1g
Magnesium stearate 1.4g
Pulvis Talci 3.0g
Preparation technology
(1) the 22.35g ferrous fumarate and folic acid pharmaceutical composition liposome that contains of embodiment 2 preparations is pulverized, crossed 80 mesh sieves, standby;
(2) take by weighing 44g microcrystalline Cellulose, 60g lactose, 6g low-substituted hydroxypropyl cellulose, cross 80 mesh sieves, mix, standby;
(3) with above-mentioned supplementary material mix homogeneously, add 2% hypromellose, 50% alcoholic solution system soft material, to cross 20 mesh sieves and granulate, 55 ℃ of oven dry add 1.4g magnesium stearate and 3.0g Pulvis Talci mix homogeneously, and 18 mesh sieve granulate get the ferrous fumarate and folic acid granule;
(4), make the tablet of ferrous fumarate and folic acid pharmaceutical composition with the dried granules tabletting.
Comparative Examples 4
The preparation of the tablet of ferrous fumarate and folic acid pharmaceutical composition
Select the ferrous fumarate and folic acid medicine 22.35g (containing ferrous fumarate 22g, the liposome 0.35g of folate composition) of Comparative Examples 2 for use
Microcrystalline Cellulose 44g
Lactose 60g
Low-substituted hydroxypropyl cellulose 6g
Hypromellose 1g
Magnesium stearate 1.4g
Pulvis Talci 3.0g
Preparation technology is with embodiment 4, and the liposome that adopts Comparative Examples 2 preparations makes the tablet of ferrous fumarate and folic acid pharmaceutical composition as active component.
Comparative Examples 5The capsule that the embodiment 1 of employing prior art CN101278922A makes.
The mensuration of test example 1 envelop rate
Get the Liposomal formulation of embodiment 1-2 and Comparative Examples 1-2 preparation, the total content that high performance liquid chromatography detects ferrous fumarate and folic acid 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, the liposome of getting the ferrous fumarate and folic acid pharmaceutical composition that embodiment 1-2 and Comparative Examples 1-2 obtain respectively is dissolved in water, make the solution that every 1ml contains the about 35 μ g of folic acid, get solution 1.3ml respectively and add the chromatographic column top, with phosphate buffer 50ml eluting, flow velocity 0.8ml/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 ferrous fumarate and folic acid.
Envelop rate %=M1/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.
The detection of test example 2 particle diameters
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 600-900nm.
Test example 3 study on the stability
With the sample of the embodiment 3-4 among the present invention and Comparative Examples 3-5 preparation accelerated test 6 months under 40 ℃ of high temperature, relative humidity 75% ± 5% condition, detect the variation of every leading indicator, the results are shown in Table 3.
Table 3 accelerated test result
By above experimental result as seen, the sample dissolution height of embodiment of the invention 3-4 preparation, good stability quickened after 6 months, and every detection index does not almost have obvious variation; Further proof product of the present invention can steadily discharge.And the sample dissolution of Comparative Examples 3-5 preparation is low, poor stability, and it is bigger to quicken after 6 months every change detected.
Particular of the present invention is in above description, is to be understood that for those skilled in the art can obtain multiplely to be equal to, to modify, to replace and change at this point, and do not deviate from the spirit and scope of the present invention described in the accessory claim.
Claims (10)
1, a kind of liposome of ferrous fumarate and folic acid pharmaceutical composition is characterized in that the component that comprises the weight portion meter is: 1883.5～120 parts of ferrous fumarate 12-36 part, folic acid 0.01-0.7 part, hydrogenated soy phosphatidyl choline 20-150 part, cholesterol 5-100 part, polyglycerin ester 3-90 part and poloxamers.
2, liposome according to claim 1 is characterized in that comprising the component of weight portion meter: 188 30 parts of 22 parts of ferrous fumarate, 0.35 part in folic acid, 50 parts of hydrogenated soy phosphatidyl cholines, 13 parts in cholesterol, 18 parts of polyglycerin ester and poloxamers.
3, according to each described liposome of claim 1-2, it is characterized in that making by the method that comprises the steps: (1) is dissolved in hydrogenated soy phosphatidyl choline, cholesterol, polyglycerin ester and poloxamer 188 in the solvent, mix homogeneously, removing desolvates makes immobilized artificial membrane; (2) add the buffer salt solution stirring and make the complete aquation of immobilized artificial membrane, make the blank liposome suspension; (3) ferrous fumarate and folic acid are dispersed in the water, add in the blank liposome suspension, make liposome turbid liquor; (4), promptly get the liposome of ferrous fumarate and folic acid pharmaceutical composition with suspension lyophilization or spray drying.
4, according to each described liposome of claim 1-3, wherein said buffer salt solution is the pharmaceutically acceptable buffer salt solution of pH value 4.5～5.5, and described buffer salt solution is selected from one or more in phosphate buffer, citrate buffer, carbonate buffer solution, borate buffer solution, the acetate buffer; Adding described buffer salt solution is 300～1000 weight portions.
5, according to each described liposome of claim 1-4, wherein said solvent is an organic solvent, be selected from ethanol, methanol, the tert-butyl alcohol, n-butyl alcohol, isopropyl alcohol, acetone, ether, benzyl alcohol, the normal hexane one or more, preferred solvent is a n-butyl alcohol.
6, according to each described liposome of claim 1-5, wherein, add the buffer salt solution stirring in the step (2) and make the complete aquation of immobilized artificial membrane, reuse tissue mashing machine spares matter emulsifying, becomes liposome turbid liquor; Perhaps, wherein in the step (3) ferrous fumarate and folic acid are dispersed in the water, add in the blank liposome suspension, be incubated 55-65 ℃, reuse tissue mashing machine spares matter emulsifying 10-30min, gets liposome turbid liquor.
7, a kind of solid preparation of ferrous fumarate and folic acid is characterized in that comprising the liposome and the pharmaceutically acceptable excipient of each described ferrous fumarate and folic acid pharmaceutical composition of claim 1-6; Described solid preparation agent comprises following component by weight: 1 part of the liposome of ferrous fumarate and folic acid pharmaceutical composition, 0.2～1.5 part of filler, 0.01～0.5 part of disintegrating agent, 0.01～0.2 part of binding agent, 0.01～0.3 part of lubricant.
8, the solid preparation of ferrous fumarate and folic acid pharmaceutical composition according to claim 7, wherein: described filler is selected from one or more in starch, microcrystalline Cellulose, lactose, 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, the cross-linking sodium carboxymethyl cellulose; Perhaps described binding agent is selected from one or more in 30 POVIDONE K 30 BP/USP 30, hypromellose, starch slurry, the sodium carboxymethyl cellulose; Perhaps described lubricant is selected from one or more in magnesium stearate, Pulvis Talci, colloidality silicon dioxide, PEG6000, the sodium lauryl sulphate etc.
9, a kind of method for preparing the solid preparation of each described ferrous fumarate of claim 7-8 and folic acid pharmaceutical composition, it comprises the steps: (1) liposome pulverizing with ferrous fumarate and folic acid pharmaceutical composition, crosses 80 mesh sieves, and is standby; (2) filler, disintegrating agent 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), make the tablet of ferrous fumarate and folic acid pharmaceutical composition with the dried granules tabletting.
10, the application of the liposome of each described ferrous fumarate and folic acid pharmaceutical composition of claim 1-6 in the medicine of preparation treatment anemia.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910017860A CN101632675A (en) | 2009-08-14 | 2009-08-14 | Ferrous fumarate and folic acid pharmaceutical composition and liposome solid preparation thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910017860A CN101632675A (en) | 2009-08-14 | 2009-08-14 | Ferrous fumarate and folic acid pharmaceutical composition and liposome solid preparation thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101632675A true CN101632675A (en) | 2010-01-27 |
Family
ID=41592115
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200910017860A Pending CN101632675A (en) | 2009-08-14 | 2009-08-14 | Ferrous fumarate and folic acid pharmaceutical composition and liposome solid preparation thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101632675A (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102670508A (en) * | 2011-03-07 | 2012-09-19 | 江苏凯吉生物科技有限公司 | Stable liposome and preparation method thereof |
| CN105796565A (en) * | 2014-12-30 | 2016-07-27 | 北京斯利安药业有限公司 | Ferrous fumarate folic acid solid preparation and preparation method thereof |
| CN106389369A (en) * | 2015-07-31 | 2017-02-15 | 安徽华明制药有限公司 | Ferrous fumarate folic acid compound film coated tablet preparation method |
| CN107348514A (en) * | 2017-06-29 | 2017-11-17 | 安徽康博特保健食品有限公司 | A kind of preparation method of low-sugar type iron Couteat of Folic Acid |
| IT201600116948A1 (en) * | 2016-11-18 | 2018-05-18 | Pharmaxima S R L | COMPOSITION OF SMOKED IRON AND ITS USE AS A FOOD SUPPLEMENT |
| CN115316480A (en) * | 2022-08-09 | 2022-11-11 | 无锡励成医学营养有限公司 | A soft candy containing vitamins and minerals and its preparation method |
-
2009
- 2009-08-14 CN CN200910017860A patent/CN101632675A/en active Pending
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102670508A (en) * | 2011-03-07 | 2012-09-19 | 江苏凯吉生物科技有限公司 | Stable liposome and preparation method thereof |
| CN102670508B (en) * | 2011-03-07 | 2015-10-28 | 江苏凯吉生物科技有限公司 | A kind of stable liposome and preparation method thereof |
| CN105796565A (en) * | 2014-12-30 | 2016-07-27 | 北京斯利安药业有限公司 | Ferrous fumarate folic acid solid preparation and preparation method thereof |
| CN105796565B (en) * | 2014-12-30 | 2019-05-28 | 北京斯利安药业有限公司 | A kind of ferrous fumarate and folic acid solid pharmaceutical preparation and preparation method thereof |
| CN106389369A (en) * | 2015-07-31 | 2017-02-15 | 安徽华明制药有限公司 | Ferrous fumarate folic acid compound film coated tablet preparation method |
| IT201600116948A1 (en) * | 2016-11-18 | 2018-05-18 | Pharmaxima S R L | COMPOSITION OF SMOKED IRON AND ITS USE AS A FOOD SUPPLEMENT |
| CN107348514A (en) * | 2017-06-29 | 2017-11-17 | 安徽康博特保健食品有限公司 | A kind of preparation method of low-sugar type iron Couteat of Folic Acid |
| CN115316480A (en) * | 2022-08-09 | 2022-11-11 | 无锡励成医学营养有限公司 | A soft candy containing vitamins and minerals and its preparation method |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101632675A (en) | Ferrous fumarate and folic acid pharmaceutical composition and liposome solid preparation thereof | |
| CN102451179B (en) | A kind of containing lycopene, enteric solid preparation of resveratrol or melatonin and preparation method thereof | |
| CN102579350B (en) | Pidotimod liposome solid preparation | |
| JP2000507613A (en) | DFMO containing sustained release formulation | |
| KR101800855B1 (en) | Ferroporphyrin solid dispersion and preparation method therefor | |
| WO2021238978A1 (en) | Pharmaceutical composition containing nitroxoline prodrug, and preparation method and application therefor | |
| CN101627998B (en) | Loratadine-ambroxol pharmaceutical composite and liposome solid preparation thereof | |
| CN104814923B (en) | A kind of tamsulosin hydrochloride sustained release preparation and preparation method thereof and its application | |
| CN102552134A (en) | Fat emulsion containing vitamin K1 | |
| CN106880845A (en) | A kind of dabigatran etcxilate solid dispersions enteric coated preparations and preparation method thereof | |
| CN102727460A (en) | Slow-release tablets containing felodipine and metoprolo salt, and preparation method thereof | |
| CN1984682B (en) | Solid medicinal preparation | |
| CN112587495A (en) | Aspirin and clopidogrel hydrogen sulfate compound preparation and preparation method thereof | |
| TW201513894A (en) | A pharmaceutical composition for skin external use comprising icotinib and the application thereof | |
| CN107375224A (en) | A kind of Gliclazide sustained-release tablet | |
| CN101732235B (en) | Method for preparing solid dispersion of tamoxifen citrate | |
| CN102247366B (en) | Medicinal compositionslow-releaseformulation containing Enalapril and Felodipine | |
| CN112156096B (en) | Folic acid sustained-release composition, sustained-release preparation and application thereof | |
| CN107206011A (en) | Complex capsule including Raloxifene and vitamin D or derivatives thereof | |
| CN102302470B (en) | Nitrendipine soft capsule | |
| CN115227652A (en) | Midosurin tablet and preparation method thereof | |
| CN101627986B (en) | Acedofenac-paracetamol pharmaceutical composite and liposome solid preparation thereof | |
| CN103655574A (en) | Compound ferrous succinate and folic acid composition | |
| CN102697765B (en) | Ranitidine hydrochloride/bismuth potassium citrate pharmaceutical composition solid lipid nanoparticles preparation | |
| CN102526111A (en) | Slow-release microsphere containing venenum bufonis lipoclastic substances as well as preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C57 | Notification of unclear or unknown address | ||
| DD01 | Delivery of document by public notice |
Addressee: Wang Ming Document name: Notification of Passing Preliminary Examination of the Application for Invention |
|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| DD01 | Delivery of document by public notice |
Addressee: Wang Ming Document name: Notification that Application Deemed not to be Proposed |
|
| DD01 | Delivery of document by public notice |
Addressee: Wang Ming Document name: Notification of Publication and of Entering the Substantive Examination Stage of the Application for Invention |
|
| DD01 | Delivery of document by public notice |
Addressee: Wang Ming Document name: the First Notification of an Office Action |
|
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Open date: 20100127 |