CN101953788A - Cefprozil liposome-containing dispersible tablet and preparation method thereof - Google Patents
Cefprozil liposome-containing dispersible tablet and preparation method thereof Download PDFInfo
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Abstract
The invention relates to a cefprozil liposome, a preparation method thereof and a dispersible tablet containing the same. The cefprozil liposome consists of cefprozil, hydrogenated soybean phosphatidylcholine, soya bean lecithin, cholesterol and vitamin E, wherein the weight ratio of the cefprozil to the hydrogenated soybean phosphatidylcholine to the soya bean lecithin to the cholesterol to the vitamin E is 1:1.25-5:1.25-5:2.5-10:0.1-3. The cefprozil dispersible tablet not only satisfies requirements on Chinese pharmacopoeia but also has the advantages of higher dissolution, quicker medical effect and remarkably improved bioavailability compared with the ordinary cefprozil medicament composition.
Description
Technical field
The present invention relates to a kind of cefprozil liposome, its preparation method and contain its dispersible tablet, the advantage that described Cefprozil dispersible table has is higher than common Cefprozil medicinal composition dissolution, the drug effect performance is faster, the bioavailability significance improves belongs to medical technical field.
Background technology
Acute cholecystitis is a kind of commonly encountered diseases.In China, according to the literature, occupy the 2nd of emergency case abdominal surgery illness, be only second to acute appendicitis, bore a hole to seeing than acute ileus and Peptic Ulcers more.Primary disease is more common in 35～40 years old middle age, and women's morbidity is many than the male, is more common in the women of obesity and multiple pregnancies especially.The onset of acute cholecystitis is because calculus is blocked cystic duct, causes intracapsular bile of gallbladder to be detained, secondary bacterial infection and cause acute inflammation.Morbific antibacterial mainly is escherichia coli, and minority is staphylococcus, streptococcus, typhoid fever or Salmonella paratyphi, bacillus pyocyaneus and anaerobe etc., aerobacteria can be taken place once in a while infect, and can have gas to exist in the gallbladder.Acute cholecystitis adopts non-operative treatment such as the associating antibacterial drug therapy, and majority can be cured.If patient has repeatedly history of attack or have calculus to exist, need the parturients having undergone elective cholecystectomy later on.PD is very fast during in view of the acute attack of elderly patients' cholecystitis, and the mortality rate of emergency operation is height far beyond choosing date for operation, so should undergo surgery in the catabasis.
Cefprozil is a second generation cephalosporin class medicine, has broad-spectrum antibacterial action.The bactericidal mechanism of this medicine is to hinder bacteria cell wall to synthesize.In vitro tests proves, cefprozil is obvious to the staphylococcus aureus in the gram positive aerobic bacteria (comprising the beta-lactamase-producing strain), streptococcus pneumoniae, micrococcus scarlatinae effect, to steadfast and persevering enterococcus, listerisa monocytogenes in mjme, staphylococcus epidermidis, staphylococcus saprophyticus, Warnei staphylococcus, streptococcus agalactiae, streptococcus C, D, F, G group and Streptococcus viridans tool inhibitory action; Invalid to methicillin-resistant staphylococcus and enterococcus faecalis; Bloodthirsty hemophilus influenza (comprising the beta-lactamase-producing strain), moraxelle catarrhalis (comprising the beta-lactamase-producing strain) to gram negative aerobic bacteria are extremely sensitive; Can suppress the breeding of Diversus citric acid bacteria, escherichia coli, Klebsiella Pneumoniae, Diplococcus gonorrhoeae (comprising the beta-lactamase-producing strain), proteus mirabilis, Salmonella, shigella dysenteriae and vibrio; Most bacterial strains to acinetobacter, Enterobacter, morganella morganii genus, proteus vulgaris, Providian Pseudomonas, Pseudomonas do not have antibiotic effect.Cefprozil does not have antibiotic effect to the melanin bacteroid in the anaerobe, difficult Fusobacterium, bacillus perfringens, Fusobacterium, peptostreptococcus and the certain inhibitory action of propionibacterium acnes tool to most bacillus fragilis strains.
The chemical name of cefprozil is: (6R, 7R)-7-[(R)-2-amino-2-(p-hydroxybenzene) acetylamino]-oct-2-ene-2-carboxylic acid-hydrate of 8-oxo-3-propylene-5-thia-1-azabicyclo-(4.2.0), English name is: Cefprozil, and structural formula is as follows:
Cefprozil exists cis-isomer and transisomer, and both ratios are about 9: 1.
Fast Absorption behind the cefprozil oral administration can reach the blood drug level peak value after 2 hours, and is widely distributed in vivo after the drug absorption, mainly is distributed in the interstitial fluid.Most of with prototype drainage from urine, the urine response rate 60%～79%; Renal clearance (the CL of cefprozil
R) be 1.78～2.53ml/minkg, be higher than glomerular filtration rate, the drainage of prompting cefprozil is an important channel with the active tubular secretion.The CL of cefprozil
RAccount for 2/3 of total CL, and studies show that according to the radio-labeled that in Mus, Canis familiaris L., monkey and human body, carries out, cefprozil only has a small amount of metabolite in urine and blood plasma, and can find to have 25% radioactivity in the excrement, show that there is nonrenal clearance approach (comprise metabolism and bile excretion, but based on the latter) (with reference to non-patent literature) really in cefprozil.
Cefprozil mainly is with oral form administration at present, the listing dosage form has tablet, capsule, dispersible tablet, dry suspension, granule and chewable tablet, described dosage form all is to adopt the simple cefprozil crude drug that does not add any modification to make, the dissolubility of gained preparation, stability and bioavailability are all relatively poor, can not effectively bring into play the pharmacological activity of cefprozil.Therefore, need urgent above-mentioned these problems that solve cefprozil, improve bioavailability and stability.
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, the what is more important liposome can improve Drug therapy exponential sum bioavailability, reduces drug toxicity and reduce drug side effect as pharmaceutical carrier, has reduced drug dose thus.The applicant imagines with the liposome cefprozil thus to obtain the pharmacological activity of expectation.
Phospholipid is the main component that constitutes the liposome bimolecular film, and it is inside that the hydrophilic and hydrophobic two kinds of groups in the phospholipid align into hydrophobic layer, the bilayer that hydrophilic layer is outside.The hydrophobic small molecules chemical compound can embed or be wrapped in the hydrophobic layer of phospholipid bilayer center.Cefprozil is wrapped in forms liposome in the phospholipid, can improve cefprozil Drug therapy exponential sum bioavailability, reduce drug toxicity and reduce drug side effect.
The inventor by creationary research, the cefprozil liposome that discovery selects for use the excipient of certain content and composition to make, not only drug content is higher, its envelop rate is far superior to the product of prior art, and make after the pharmaceutically acceptable dosage form, promote that medicine absorbs under one's belt, prolong drug is at the circulation time of blood, thereby also significance raising of bioavailability.
Chinese patent CN101391098A discloses a kind of melittin Liposomal formulation, it is characterized in that being made up of for 10～140 parts 1 part of melittin, phosphatidase 15～40 part, 1.3～10 parts in cholesterol, poloxamer.Prepared liposome adjuvant content is higher, and drug content is less; The overall dimensions of the pharmaceutical composition made of liposome is too big thus, is not suitable for the higher kind of drug content.
Chinese patent CN101700232A discloses a kind of Cefprozil submicron emulsion solid preparation and new application the thereof, it is characterized in that being made up of cefprozil, Ovum Gallus domesticus Flavus lecithin, poloxamer 188 and sodium deoxycholate, and prepared cefprozil submicron emulsion envelop rate is lower.
Chinese patent CN101032489A discloses a kind of Cefprozil dispersible table and preparation method thereof, and described dispersible tablet is to adopt the simple cefprozil crude drug that does not add any modification to make, and the dissolubility of gained preparation, stability and bioavailability are all relatively poor.
Cefprozil dispersible table of the present invention, once a day or twice administration in a day, the patient takes medicine very conveniently like this, has improved the compliance that the patient takes medicine, and improves patient's quality of life.
Non-patent literature: Lei Zhaobao. 9 in the new external medical antibiotic of oral cephalosporin Cefprozil., 15 (5), 1994,360-362
Patent documentation 1: U.S. Pat 4520022
Patent documentation 2: U.S. Pat 4727070
Summary of the invention
Problem to be solved by this invention is that the defective that overcomes prior art provides a kind of cefprozil liposome and preparation method thereof, and purpose is dissolution problem and the stability problem that solves cefprozil, improves the bioavailability of cefprozil and prolongs period of storage.
Another object of the present invention also is to provide a kind of dispersible tablet that comprises the cefprozil liposome and preparation method thereof, and described dispersible tablet is made up of cefprozil liposome and pharmaceutically acceptable carrier.
Another object of the present invention also is to provide a kind of cefprozil or cefprozil liposome or Cefprozil dispersible table to be used for the treatment of application in the medicine of acute cholecystitis in preparation.
The technical scheme that the present invention solves is as follows:
(1) a kind of cefprozil liposome, it is characterized in that, described cefprozil liposome is made up of cefprozil, hydrogenated soy phosphatidyl choline, soybean lecithin, cholesterol and vitamin E, wherein cefprozil: hydrogenated soy phosphatidyl choline: soybean lecithin: cholesterol: the weight ratio of vitamin E is 1: 1.25～5: 1.25～5: 2.5～10: 0.1～3.
Described cefprozil can crystallization, partially crystallizable or amorphous forms, solvate especially hydrate and polycrystalline form exist, also can laevoisomer, dextroisomer, mixing raceme or optical isomer exist.Those that Chinese patent CN101225088A, CN1694888A, CN101024649A are announced are incorporated herein by reference this in full at this.
(2) as the described cefprozil liposome of claim (1), it is characterized in that, wherein cefprozil: hydrogenated soy phosphatidyl choline: soybean lecithin: cholesterol: the weight ratio of vitamin E is 1: 2.5～5: 2.5～5: 5～10: 0.1～2.
(3) as claim (1), (2) each described cefprozil liposome, it is characterized in that, wherein cefprozil: hydrogenated soy phosphatidyl choline: soybean lecithin: cholesterol: the weight ratio of vitamin E is 1: 2.8: 2.8: 5.6: 0.8.
(4) a kind of method for preparing claim (1) to (3) each described cefprozil liposome is characterized in that described preparation method comprises:
(A) by recipe quantity hydrogenated soy phosphatidyl choline, soybean lecithin, cholesterol and vitamin E are dissolved in an amount of organic solvent, mix homogeneously filters, and evaporation is removed organic solvent and made immobilized artificial membrane, drying;
(B) take by weighing the cefprozil of recipe quantity, add an amount of pH value and be 6.0～8.0 buffer and make dissolving;
(C) add above-mentioned buffer in the dried immobilized artificial membrane and an amount of, concentration dissolved with same buffer is the 30 POVIDONE K 30 BP/USP of 0.76mg/ml
30Solution, jolting is stirred and is made the complete aquation of immobilized artificial membrane, and high speed homogenization emulsifying makes liposome turbid liquor;
(D), promptly get the cefprozil liposome with liposome turbid liquor lyophilization or spray drying.
Above-mentioned cefprozil liposome is at the organic solvent that preparation process added, and is selected from dehydrated alcohol, methanol, the tert-butyl alcohol, n-butyl alcohol, isopropyl alcohol, acetone, ether, benzyl alcohol, the normal hexane one or more; Be preferably dehydrated alcohol, isopropyl alcohol or the tert-butyl alcohol; Most preferably be dehydrated alcohol.The amount of used organic solvent is 1～50 times of cefprozil amount; Be preferably 5～30 times.
Above-mentioned cefprozil dissolves used buffer, be selected from phosphate buffer, citrate salt buffer, carbonate buffer solution, borate buffer solution, acetate buffer, the TRIS buffer one or more, the pH value of buffer is 6.0～8.0, is preferably 6.5～7.5.
In the above-mentioned preparation method, 30 POVIDONE K 30 BP/USP
30The concentration of solution is 0.5mg/ml～1.5mg/ml, is preferably 0.76mg/ml.
As the described preparation method of claim (4), it is characterized in that (5) described buffer is a phosphate buffer.
(6) a kind of Cefprozil dispersible table is characterized in that, is made up of each described cefprozil liposome of claim (1) to (5) and pharmaceutically acceptable carrier.
The dosage of wherein said cefprozil liposome is calculated as 50.00mg～500.00mg by the cephalo propylene, is preferably 75.00mg～300.00mg.
Wherein said pharmaceutically acceptable carrier is art-recognized, and refer to participate in to deliver or transport any theme composition or its component pharmaceutically acceptable material, component or carrier from the part of an organ or health to the part of another organ or health, as liquid or solid filler, diluent, excipient, solvent or encapsulating material.With theme composition and the compatible meaning of component thereof on, every kind of carrier must be acceptable and be harmless to the patient.The amount of pharmaceutically acceptable every kind of carrier in pharmaceutical composition can change in the normal ranges of this area.
As the described Cefprozil dispersible table of claim (6), it is characterized in that (7) described pharmaceutically acceptable carrier is selected from diluent, disintegrating agent, binding agent, lubricant, fluidizer, correctives, aromatic, coloring agent or dissolubility promoter.
Suitable diluent can be selected from microcrystalline Cellulose, optimize microcrystalline Cellulose, Powderd cellulose, mannitol, lactose, saccharide, sugar derivatives, calsium supplement or their combination; Calsium supplement is selected from calcium carbonate, calcium phosphate, calcium hydrogen phosphate, Malic acid citric acid calcium, Citric acid calcium, calcium malate, calcium lactate or calcium acetate;
Suitable disintegrants can be selected from carboxymethylstach sodium, polyvinylpolypyrrolidone, primojel, L-hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose, sodium carboxymethyl cellulose, dried starch or their combination;
Suitable bonding can be selected from polyvidone, hydroxypropyl emthylcellulose, hydroxypropyl cellulose, pre-paying starch, starch or their combination; Polyvidone is preferably 30 POVIDONE K 30 BP/USP 30;
Examples of suitable lubricants can be selected from magnesium stearate, calcium stearate, stearic acid, calcium silicates, Talcum or their combination;
Suitable fluidizer can be selected from micropowder silica gel, magnesium trisilicate, cellulose powder, starch, Talcum or their combination;
Suitable correctives is selected from sucrose, Icing Sugar, sucralose, steviosin, saccharin sodium, aspartame, lactose or their combination;
Suitable aromatic is selected from water quality essence, emulsifying essence, Water/oil dual-purpose essence, panchromatic essence or their combination, and wherein water quality essence is selected from strawberry essence, apple essence, flavoring banana essence, flavoring pineapple essence, flavoring orange essence, honey peach essence, Fructus Citri Limoniae essence, fragrant citrus essence, hami melon essence, Fructus Fragariae Ananssae powdered flavor, Fructus Ananadis comosi powdered flavor or their combination;
Suitable coloring agent be selected from carmine, lemon yellow, sunset yellow, amaranth, erythrosine, newly red, red pigment of cowberry, capsanthin of red, indigo, light blue, beet red, lac, red rice is red or their combination;
Suitable dissolution promoter or dissolubility promoter can be selected from polyvinylpolypyrrolidone, polyvidone, sodium lauryl sulphate, polyoxyethylene sorbitan monoleate or their combination;
Suitable solvent or wetting agent can be selected from water, ethanol, Polyethylene Glycol or ethanol water; Be preferably water or ethanol water; Ethanol water is preferably 30%～90% ethanol water.
(8) as the described Cefprozil dispersible table of claim (6), it is characterized in that described Cefprozil dispersible table comprises following components in part by weight: cefprozil: diluent: disintegrating agent: binding agent: lubricant: fluidizer: correctives: aromatic: coloring agent: dissolubility promoter=1: 0.1～30: 0.01～10: 0.01～5: 0～5: 0～5: 0～20: 0～1: 0～1: 0～10.
(9) a kind of method for preparing claim (6) to (8) each described Cefprozil dispersible table is characterized in that described preparation method comprises:
(A) press recipe quantity the cefprozil liposome is pulverized, sieve;
(B) by recipe quantity with the pulverizing of sieving respectively of various pharmaceutically acceptable carriers, standby;
(C) get in the water-soluble or ethanol-water solution of the binding agent of recipe quantity, make 2～15% adhesive solution, use as binding agent;
The cefprozil liposome that (D) will sieve and diluent, disintegrating agent, correctives add in the above-mentioned adhesive solution makes soft material, the granulation of sieving, and oven dry, granulate makes cefprozil liposome particles I, and is standby;
(E) with cefprozil liposome particles I and the disintegrating agent that has sieved, lubricant, fluidizer in the three-dimensional movement mixer by the equivalent method mix homogeneously that progressively increases, make cefprozil liposome particles II, standby;
(F) drug content in the mensuration cefprozil liposome particles II, it is heavy to calculate sheet;
(G) use rotary tablet machine that cefprozil liposome particles II is pressed into dispersible tablet.
Wherein said ethanol-water solution is 30%～90% ethanol-water solution, is preferably 30%～50% ethanol-water solution
(10) each described cefprozil liposome of claim (1) to (3) or each described Cefprozil dispersible table of claim (6) to (8) are used for the treatment of application in the medicine of acute cholecystitis in preparation.
The dispersible tablet that comprises the cefprozil liposome of the present invention not only meets the Chinese Pharmacopoeia requirement, and has advantage higher than common Cefprozil medicinal composition dissolution, that the drug effect performance is faster, the bioavailability significance improves.Owing to cefprozil of the present invention is adopted the form of liposome, and to preparation technology's research control, realized the targeted delivery of medicine, can make medicine arrive gastrointestinal tract mucous cell quickly and accurately, thereby performance curative effect, improved bioavailability, brought convenience to clinical application.
Compare with prior art, cefprozil liposome dispersible tablet provided by the invention has following unforeseeable technique effect:
(1) cefprozil liposome of the present invention, envelop rate is higher, and its envelop rate surpasses 80%;
(2) cefprozil liposome of the present invention is more stable, and percolation ratio is lower, has antioxidant effect simultaneously;
(3) dispersible tablet that comprises the cefprozil liposome of the present invention, not only stability and bioavailability are higher than prior art products far away, and bring great convenience to clinical application;
(4) dispersible tablet that comprises the cefprozil liposome of the present invention has been avoided the peak valley phenomenon in the drug release process, has the permanent effect of slow release, can bring into play drug action more fully, and toxic and side effects is little;
(5) cefprozil liposome interior of the present invention is added with dissolution or dissolubility promoter such as 30 POVIDONE K 30 BP/USP
30, the outside also is added with dissolution or dissolubility promoter such as 30 POVIDONE K 30 BP/USP
30Or polyvinylpolypyrrolidone, bioavailability is further enhanced;
(6) adopt conventional process equipment, but commercial scale, high efficiency production, and constant product quality is a kind of uniqueness and blanket, low-cost industrial preparation method.
The dispersible tablet that comprises the cefprozil liposome provided by the invention is carried out stability test to be investigated: placed respectively 10 days under high temperature is 60 ℃, high humility (relative humidity 90% scholar 5%), illumination 4500LX condition, every detection index has no significant change; Carried out accelerated test 6 months under temperature is 40 ℃, relative humidity 75% scholar 5% condition, every detection index does not all have significant change; In temperature is that 25 ℃, relative humidity are to carry out long term test 12 months under 60% scholar, 10% condition, and every detection index does not all have significant change.
The dispersible tablet that comprises the cefprozil liposome provided by the invention carries out acute toxicity test and abnormal toxicity test inspection, and the result is all up to specification, and safety obtains proof.
The specific embodiment
Describe the present invention in detail below in conjunction with embodiment.
Embodiment 1: the preparation of cefprozil liposome
| The supplementary material title | Dosage 1 (mg) | Dosage 2 (mg) | Dosage 3 (mg) |
| Cefprozil | 62.50 | 125.00 | 250.00 |
| Hydrogenated soy phosphatidyl choline | 156.25 | 312.50 | 625.00 |
| Soybean lecithin | 156.25 | 312.50 | 625.00 |
| Cholesterol | 312.50 | 625.00 | 1250.00 |
| Vitamin E | 50.00 | 100.00 | 200.00 |
| Amount to | 737.50 | 1475.00 | 2950.00 |
Preparation method:
(A) by recipe quantity hydrogenated soy phosphatidyl choline, soybean lecithin, cholesterol and vitamin E are dissolved in an amount of dehydrated alcohol, mix homogeneously filters, and evaporation is removed dehydrated alcohol and made immobilized artificial membrane, the vacuum decompression drying on rotary evaporator.The amount of used dehydrated alcohol is 30 times of cefprozil amount.
(B) take by weighing the cefprozil of recipe quantity, add an amount of pH value and be 7.0 phosphate buffer and make dissolving.
(C) add above-mentioned buffer in the dried immobilized artificial membrane and an amount of, concentration dissolved with same buffer is the 30 POVIDONE K 30 BP/USP of 0.76mg/ml
30Solution, jolting is stirred and is made the complete aquation of immobilized artificial membrane, and high speed homogenization emulsifying makes liposome turbid liquor.The amount of used buffer is 20 times of cefprozil amount.
Wherein set high pressure homogenizer first class pressure normal pressure, secondary pressure 65bar circulation primary; First class pressure 300bar, secondary pressure 65bar circulation primary; Twice of first class pressure 500bar, secondary pressure 70bar circulation; Twice of first class pressure 650bar, secondary pressure 70bar circulation; Whole process temperature is controlled at 45 ℃.
The average particle size distribution of checking liposome turbid liquor is in 150～300nm; If the particle mean size of liposome turbid liquor, is set high pressure homogenizer first class pressure 800bar recirculation 1 time greater than 300nm.
(D) with liposome turbid liquor lyophilization on one freezer dryer, promptly get the cefprozil liposome.
Embodiment 2: the preparation of cefprozil liposome
| The supplementary material title | Dosage 1 (mg) | Dosage 2 (mg) | Dosage 3 (mg) |
| Cefprozil | 62.50 | 125.00 | 250.00 |
| Hydrogenated soy phosphatidyl choline | 175.00 | 350.00 | 700.00 |
| Soybean lecithin | 175.00 | 350.00 | 700.00 |
| Cholesterol | 350.00 | 700.00 | 1400.00 |
| Vitamin E | 50.00 | 100.00 | 200.00 |
| Amount to | 812.50 | 1625.00 | 3250.00 |
Preparation method:
(A) by recipe quantity hydrogenated soy phosphatidyl choline, soybean lecithin, cholesterol and vitamin E are dissolved in an amount of dehydrated alcohol, mix homogeneously filters, and evaporation is removed dehydrated alcohol and made immobilized artificial membrane, the vacuum decompression drying on rotary evaporator.The amount of used dehydrated alcohol is 30 times of cefprozil amount.
(B) take by weighing the cefprozil of recipe quantity, add an amount of pH value and be 7.5 phosphate buffer and make dissolving.
(C) add above-mentioned buffer in the dried immobilized artificial membrane and an amount of, concentration dissolved with same buffer is the 30 POVIDONE K 30 BP/USP of 0.76mg/ml
30Solution, jolting is stirred and is made the complete aquation of immobilized artificial membrane, and high speed homogenization emulsifying makes liposome turbid liquor.The amount of used buffer is 20 times of cefprozil amount.
Wherein set high pressure homogenizer first class pressure normal pressure, secondary pressure 60bar circulation primary; First class pressure 300bar, secondary pressure 60bar circulation primary; Twice of first class pressure 500bar, secondary pressure 65bar circulation; Twice of first class pressure 650bar, secondary pressure 65bar circulation; Whole process temperature is controlled at 45 ℃.
The average particle size distribution of checking liposome turbid liquor is in 150～300nm; If the particle mean size of liposome turbid liquor, is set high pressure homogenizer first class pressure 800bar recirculation 1 time greater than 300nm.
(D) with liposome turbid liquor spray drying on one spray dryer, promptly get the cefprozil liposome.
Embodiment 3: the preparation of cefprozil liposome
| The supplementary material title | Dosage 1 (mg) | Dosage 2 (mg) | Dosage 3 (mg) |
| Cefprozil | 62.50 | 125.00 | 250.00 |
| Hydrogenated soy phosphatidyl choline | 312.50 | 625.00 | 1250.00 |
| Soybean lecithin | 312.50 | 625.00 | 1250.00 |
| Cholesterol | 625.00 | 1250.00 | 2500.00 |
| Vitamin E | 50.00 | 100.00 | 200.00 |
| Amount to | 1362.50 | 2725.00 | 5450.00 |
Preparation method:
(A) by recipe quantity hydrogenated soy phosphatidyl choline, soybean lecithin, cholesterol and vitamin E are dissolved in an amount of dehydrated alcohol, mix homogeneously filters, and evaporation is removed dehydrated alcohol and made immobilized artificial membrane, the vacuum decompression drying on rotary evaporator.The amount of used dehydrated alcohol is 30 times of cefprozil amount.
(B) take by weighing the cefprozil of recipe quantity, add an amount of pH value and be 8.0 phosphate buffer and make dissolving.
(C) add above-mentioned buffer in the dried immobilized artificial membrane and an amount of, concentration dissolved with same buffer is the 30 POVIDONE K 30 BP/USP of 0.76mg/ml
30Solution, jolting is stirred and is made the complete aquation of immobilized artificial membrane, and high speed homogenization emulsifying makes liposome turbid liquor.The amount of used buffer is 20 times of cefprozil amount.
Wherein set high pressure homogenizer first class pressure normal pressure, secondary pressure 60bar circulation primary; First class pressure 300bar, secondary pressure 60bar circulation primary; Twice of first class pressure 500bar, secondary pressure 70bar circulation; Twice of first class pressure 700bar, secondary pressure 70bar circulation; Whole process temperature is controlled at 45 ℃.
The average particle size distribution of checking liposome turbid liquor is in 150～300nm; If the particle mean size of liposome turbid liquor, is set high pressure homogenizer first class pressure 800bar recirculation 1 time greater than 300nm.
(D) with liposome turbid liquor lyophilization on one freezer dryer, promptly get the cefprozil liposome.
Embodiment 4: the dispersible tablet that comprises the cefprozil liposome
| The supplementary material title | Dosage 1 (mg) | Dosage 2 (mg) | Dosage 3 (mg) |
| Cefprozil liposome * | 62.50 | 125.00 | 250.00 |
| Optimize microcrystalline Cellulose | 62.75 | 125.50 | 251.00 |
| Sucralose | 3.00 | 6.00 | 12.00 |
| Polyvinylpolypyrrolidone | 3.75 | 7.50 | 15.00 |
| Carboxymethylstach sodium | 6.00 | 12.00 | 24.00 |
| Magnesium stearate | 3.00 | 6.00 | 12.00 |
| Micropowder silica gel | 1.50 | 3.00 | 6.00 |
| 30 POVIDONE K 30 BP/USP 30 | 7.50 | 15.00 | 30.00 |
| 30% alcoholic solution | In right amount | In right amount | In right amount |
| Sheet is heavy | 150.00 | 300.00 | 600.00 |
* get the cefprozil liposome of embodiment 1 preparation, dosage is pressed the cephalo propylene and is calculated.
Preparation method:
(A) press recipe quantity the cefprozil liposome is pulverized, cross 80 mesh sieves;
(B) press recipe quantity and will optimize microcrystalline Cellulose, carboxymethylstach sodium, polyvinylpolypyrrolidone, sucralose, magnesium stearate and micropowder silica gel 100 mesh sieves pulverizing excessively respectively, standby;
(C) 30 POVIDONE K 30 BP/USP 30 of getting recipe quantity is dissolved in the 30% an amount of alcoholic solution, makes 10% 30 POVIDONE K 30 BP/USP 30 alcoholic solution, uses as binding agent;
Cefprozil liposome that (D) will sieve and microcrystalline Cellulose, polyvinylpolypyrrolidone, sucralose are made soft material in 30 POVIDONE K 30 BP/USP 30 alcoholic solution of adding 10%, and cross 24 mesh sieves and granulate, 60 ℃ of oven dry, 18 order granulate make cefprozil liposome particles I;
(E) with cefprozil liposome particles I and the carboxymethylstach sodium that has sieved, magnesium stearate, micropowder silica gel in the three-dimensional movement mixer by the equivalent method mix homogeneously that progressively increases, make cefprozil liposome particles II, standby;
(F) drug content in the mensuration cefprozil liposome particles II, it is heavy to calculate sheet;
(G) use rotary tablet machine that the cefprozil liposome particles is pressed into dispersible tablet, make 10000, promptly.
Embodiment 5: the dispersible tablet that comprises the cefprozil liposome
| The supplementary material title | Dosage 1 (mg) | Dosage 2 (mg) | Dosage 3 (mg) |
| Cefprozil liposome * | 62.50 | 125.00 | 250.00 |
| Optimize microcrystalline Cellulose | 64.25 | 128.50 | 257.00 |
| Sucralose | 3.00 | 6.00 | 12.00 |
| Polyvinylpolypyrrolidone | 3.75 | 7.50 | 15.00 |
| Carboxymethylstach sodium | 4.50 | 9.00 | 18.00 |
| Magnesium stearate | 3.00 | 6.00 | 12.00 |
| Micropowder silica gel | 1.50 | 3.00 | 6.00 |
| 30 POVIDONE K 30 BP/USP 30 | 7.50 | 15.00 | 30.00 |
| 50% alcoholic solution | In right amount | In right amount | In right amount |
| Sheet is heavy | 150.00 | 300.00 | 600.00 |
* get the cefprozil liposome of embodiment 2 preparations, dosage is pressed the cephalo propylene and is calculated.
Preparation method:
(A) press recipe quantity the cefprozil liposome is pulverized, cross 80 mesh sieves;
(B) press recipe quantity and will optimize microcrystalline Cellulose, carboxymethylstach sodium, polyvinylpolypyrrolidone, sucralose, magnesium stearate and micropowder silica gel 100 mesh sieves pulverizing excessively respectively, standby;
(C) 30 POVIDONE K 30 BP/USP 30 of getting recipe quantity is dissolved in the 50% an amount of alcoholic solution, makes 10% 30 POVIDONE K 30 BP/USP 30 alcoholic solution, uses as binding agent;
Cefprozil liposome that (D) will sieve and microcrystalline Cellulose, polyvinylpolypyrrolidone, sucralose are made soft material in 30 POVIDONE K 30 BP/USP 30 alcoholic solution of adding 10%, and cross 30 mesh sieves and granulate, 60 ℃ of oven dry, 18 order granulate make cefprozil liposome particles I;
(E) with cefprozil liposome particles I and the carboxymethylstach sodium that has sieved, magnesium stearate, micropowder silica gel in the three-dimensional movement mixer by the equivalent method mix homogeneously that progressively increases, make cefprozil liposome particles II, standby;
(F) drug content in the mensuration cefprozil liposome particles II, it is heavy to calculate sheet;
(G) use rotary tablet machine that the cefprozil liposome particles is pressed into dispersible tablet, make 10000, promptly.
Embodiment 6: the dispersible tablet that comprises the cefprozil liposome
| The supplementary material title | Dosage 1 (mg) | Dosage 2 (mg) | Dosage 3 (mg) |
| Cefprozil liposome * | 62.50 | 125.00 | 250.00 |
| Optimize microcrystalline Cellulose | 63.50 | 127.00 | 254.00 |
| Sucralose | 3.00 | 6.00 | 12.00 |
| Polyvinylpolypyrrolidone | 3.00 | 6.00 | 12.00 |
| Carboxymethylstach sodium | 6.00 | 12.00 | 24.00 |
| Magnesium stearate | 3.00 | 6.00 | 12.00 |
| Micropowder silica gel | 1.50 | 3.00 | 6.00 |
| 30 POVIDONE K 30 BP/USP 30 | 7.50 | 15.00 | 30.00 |
| 30% alcoholic solution | In right amount | In right amount | In right amount |
| Sheet is heavy | 150.00 | 300.00 | 600.00 |
* get the cefprozil liposome of embodiment 3 preparations, dosage is pressed the cephalo propylene and is calculated.
Preparation method:
(A) press recipe quantity the cefprozil liposome is pulverized, cross 80 mesh sieves;
(B) press recipe quantity and will optimize microcrystalline Cellulose, carboxymethylstach sodium, polyvinylpolypyrrolidone, sucralose, magnesium stearate and micropowder silica gel 100 mesh sieves pulverizing excessively respectively, standby;
(C) 30 POVIDONE K 30 BP/USP 30 of getting recipe quantity is dissolved in the 30% an amount of alcoholic solution, makes 10% 30 POVIDONE K 30 BP/USP 30 alcoholic solution, uses as binding agent;
Cefprozil liposome that (D) will sieve and microcrystalline Cellulose, polyvinylpolypyrrolidone, sucralose are made soft material in 30 POVIDONE K 30 BP/USP 30 alcoholic solution of adding 10%, and cross 20 mesh sieves and granulate, 60 ℃ of oven dry, 16 order granulate make cefprozil liposome particles I;
(E) with cefprozil liposome particles I and the carboxymethylstach sodium that has sieved, magnesium stearate, micropowder silica gel in the three-dimensional movement mixer by the equivalent method mix homogeneously that progressively increases, make cefprozil liposome particles II, standby;
(F) drug content in the mensuration cefprozil liposome particles II, it is heavy to calculate sheet;
(G) use rotary tablet machine that the cefprozil liposome particles is pressed into dispersible tablet, make 10000, promptly.
Embodiment 7: the mensuration of envelop rate
Get the sample (control sample 1 and control sample 2) of embodiment 1 and embodiment 3 preparations among the cefprozil liposome of the embodiment of the invention 1～3 preparation and the patent documentation CN101700232A and carry out the mensuration of envelop rate, the total content that high performance liquid chromatography detects cefprozil is M, selects for use column chromatography to separate liposome.
Get 1.5g sephadex G-50, soak swelling more than 12 hours with the pH7.8 phosphate buffer, pack in the chromatographic column (200mm * 10mm), with above-mentioned phosphate buffer flushing balance, get the cefprozil liposome that embodiment 1～5 makes, add water and make dissolving, make the solution that contains cefprozil 10mg among every 1ml approximately, get solution 1.0ml respectively, add the chromatographic column top, with above-mentioned phosphate buffer 50ml eluting, flow velocity 1.2ml/min, the eluent of collecting adds rupture of membranes agent (ethanol: 50ml benzyl alcohol=8: 1), mixing, the content M1 of high performance liquid chromatography detection cefprozil.
Envelop rate %=M1/M * 100%.
Investigate 0,1,3,6,12 month respectively, result such as following table:
Result of the test shows that the envelop rate of the sample of the embodiment of the invention 1～3 preparation all reaches more than 80%, and wherein the envelop rate of embodiment 2 reaches 83%, and the envelop rate of embodiment 3 reaches 91%; And the envelop rate of control sample 1 has only 75%, and the envelop rate of control sample 2 is 80%, illustrates that by the envelop rate of cefprozil liposome of the present invention comparison product 1, control sample 2 taller in the same old way its superiority is arranged.
Embodiment 8: study on the stability
The sample (control sample 3) of getting embodiment 6 preparations among the cefprozil liposome of the embodiment of the invention 1～3 preparation and the patent documentation CN101700232A is that 40 ± 2 ℃, relative humidity are to place 6 months under 75 ± 5% the condition in temperature, carry out accelerated test, respectively at sampling at 0,1,2,3,6 the end of month once, measure by the high spot reviews project, the results are shown in following table:
Result of the test shows, the every detection index of sample of the embodiment of the invention 4～6 preparations does not all have obvious variation, and related substance comparison product 3 also low in the same old way, dissolution comparison is product 3 height in the same old way, and illustrate by the Cefprozil dispersible table of cefprozil liposome preparation of the present invention has superiority in raising aspect stable.
Obviously, the above embodiment of the present invention only is for example of the present invention clearly is described, and is not to be qualification to embodiments of the present invention.For those of ordinary skill in the field, can also make other changes in different forms on the basis of the above description.Here need not also can't give exhaustive to all embodiments.And these belong to conspicuous variation or the change that spirit of the present invention extended out and still are among protection scope of the present invention.
Should be understood that in addition in the present invention mentioned all publications and patent here all to be incorporated herein by reference, just quoted as a reference separately as each piece document.
Claims (10)
1. cefprozil liposome, it is characterized in that, described cefprozil liposome is made up of cefprozil, hydrogenated soy phosphatidyl choline, soybean lecithin, cholesterol and vitamin E, wherein cefprozil: hydrogenated soy phosphatidyl choline: soybean lecithin: cholesterol: the weight ratio of vitamin E is 1: 1.25～5: 1.25～5: 2.5～10: 0.1～3.
2. cefprozil liposome as claimed in claim 1 is characterized in that, wherein cefprozil: hydrogenated soy phosphatidyl choline: soybean lecithin: cholesterol: the weight ratio of vitamin E is 1: 2.5～5: 2.5～5: 5～10: 0.1～2.
3. as claim 1,2 each described cefprozil liposomees, it is characterized in that, wherein cefprozil: hydrogenated soy phosphatidyl choline: soybean lecithin: cholesterol: the weight ratio of vitamin E is 1: 2.8: 2.8: 5.6: 0.8.
4. a method for preparing each described cefprozil liposome of claim 1 to 3 is characterized in that, described preparation method comprises:
(A) by recipe quantity hydrogenated soy phosphatidyl choline, soybean lecithin, cholesterol and vitamin E are dissolved in an amount of organic solvent, mix homogeneously filters, and evaporation is removed organic solvent and made immobilized artificial membrane, drying;
(B) take by weighing the cefprozil of recipe quantity, add an amount of pH value and be 6.0～8.0 buffer and make dissolving;
(C) add above-mentioned buffer in the dried immobilized artificial membrane and an amount of, concentration dissolved with same buffer is the 30 POVIDONE K 30 BP/USP of 0.76mg/ml
30Solution, jolting is stirred and is made the complete aquation of immobilized artificial membrane, and high speed homogenization emulsifying makes liposome turbid liquor;
(D), promptly get the cefprozil liposome with liposome turbid liquor lyophilization or spray drying.
5. preparation method as claimed in claim 4 is characterized in that, described buffer is a phosphate buffer.
6. a Cefprozil dispersible table is characterized in that, is made up of each described cefprozil liposome of claim 1 to 5 and pharmaceutically acceptable carrier.
7. Cefprozil dispersible table as claimed in claim 6 is characterized in that, described pharmaceutically acceptable carrier is selected from diluent, disintegrating agent, binding agent, lubricant, fluidizer, correctives, aromatic, coloring agent or dissolubility promoter.
8. Cefprozil dispersible table as claimed in claim 6, it is characterized in that described Cefprozil dispersible table comprises following components in part by weight: cefprozil: diluent: disintegrating agent: binding agent: lubricant: fluidizer: correctives: aromatic: coloring agent: dissolubility promoter=1: 0.1～30: 0.01～10: 0.01～5: 0～5: 0～5: 0～20: 0～1: 0～1: 0～10.
9. a method for preparing each described Cefprozil dispersible table of claim 6 to 8 is characterized in that, described preparation method comprises:
(A) press recipe quantity the cefprozil liposome is pulverized, sieve;
(B) by recipe quantity with the pulverizing of sieving respectively of various pharmaceutically acceptable carriers, standby;
(C) get in the water-soluble or ethanol-water solution of the binding agent of recipe quantity, make 2～15% adhesive solution, use as binding agent;
The cefprozil liposome that (D) will sieve and diluent, disintegrating agent, correctives add in the above-mentioned adhesive solution makes soft material, the granulation of sieving, and oven dry, granulate makes cefprozil liposome particles I, and is standby;
(E) with cefprozil liposome particles I and the disintegrating agent that has sieved, lubricant, fluidizer in the three-dimensional movement mixer by the equivalent method mix homogeneously that progressively increases, make cefprozil liposome particles II, standby;
(F) drug content among the mensuration cefprozil liposome particles II, it is heavy to calculate sheet;
(G) use rotary tablet machine that cefprozil liposome particles II is pressed into dispersible tablet.
10. each described cefprozil liposome of claim 1 to 3 or each described Cefprozil dispersible table of claim 6 to 8 are used for the treatment of application in the medicine of acute cholecystitis in preparation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010102020181A CN101953788A (en) | 2010-06-17 | 2010-06-17 | Cefprozil liposome-containing dispersible tablet and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010102020181A CN101953788A (en) | 2010-06-17 | 2010-06-17 | Cefprozil liposome-containing dispersible tablet and preparation method thereof |
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| Publication Number | Publication Date |
|---|---|
| CN101953788A true CN101953788A (en) | 2011-01-26 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103110596A (en) * | 2012-12-31 | 2013-05-22 | 广东博洲药业有限公司 | Cefprozil dispersible tablet and preparation method thereof |
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- 2010-06-17 CN CN2010102020181A patent/CN101953788A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103110596A (en) * | 2012-12-31 | 2013-05-22 | 广东博洲药业有限公司 | Cefprozil dispersible tablet and preparation method thereof |
| CN103110596B (en) * | 2012-12-31 | 2014-06-25 | 广东博洲药业有限公司 | Cefprozil dispersible tablet and preparation method thereof |
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