CN108113972A - A kind of pharmaceutical composition containing cefteram pivoxil - Google Patents

A kind of pharmaceutical composition containing cefteram pivoxil Download PDF

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CN108113972A
CN108113972A CN201810192145.4A CN201810192145A CN108113972A CN 108113972 A CN108113972 A CN 108113972A CN 201810192145 A CN201810192145 A CN 201810192145A CN 108113972 A CN108113972 A CN 108113972A
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cefteram pivoxil
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pharmaceutical composition
cefteram
pivoxil
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不公告发明人
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
    • A61K31/546—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention discloses a kind of pharmaceutical compositions containing cefteram pivoxil, it is used as gel inhibitor by adding in sodium propionate in the composition, effectively inhibit the phenomenon that its solid pharmaceutical preparation is gelled in aqueous solution, effectively increase the dissolving out capability of solid pharmaceutical preparation, and then improve bioavilability.And the collaboration flavored action of sodium propionate and Aspartame is utilized, the bitterness problem for solving granular preparation.By dry granulation process, the introducing of the undesirable elements such as moisture, high temperature is avoided, coordinates preparation prescription, solves ester bond in bulk pharmaceutical chemicals molecule, amido bond, the hydrolysis of lactam bond and primary amine groups or oxidative degradation problem.Experiment proves, works well.

Description

A kind of pharmaceutical composition containing cefteram pivoxil
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to a kind of pharmaceutical composition containing cefteram pivoxil and its Preparation method.
Background technology
Cefteram pivoxil is third generation oral cephalosporin, is precursor medicine of the Cefteram through ester group structural modification Object, activity itself is weaker, generates active Cefteram through esterase hydrolyzed after oral absorption and generates antibacterial activity.To citric acid fungus The Grain-negatives such as category, Serratia and Enterobacter and positive bacteria have broad-spectrum antibacterial action.Clinic is mainly used for streptococcus, pneumonia Infection caused by coccus, Escherichia coli, Klebsiella, proteus and haemophilus influenzae etc., such as sphagitis, tonsil Inflammation, bronchitis, pneumonia, pyelonephritis, cystitis, gonococcal urethritis, cholecystitis, tympanitis and scarlet fever etc..
Cefteram pivoxil mechanism of action is the synthesis for blocking bacteria cell wall, cefteram pivoxil and penicillin knot In hop protein (PBP) 3,1A, 1Bs have very strong associativity, so as to play bactericidal effect.Cefteram pivoxil is blue to leather Family name's positive bacteria and Gram-negative bacteria have antibacterial action.Especially in gram-positive bacteria streptococcus, pneumococcus, leather Escherichia coli, Klebsiella, gonococcus, haemophilus influenzae and anaerobic bacteria Streptococcus pyrogenes category in Lan Shi negative bacteriums etc. are more The very strong antibacterial action of display.To took orally in the past the insensitive Serratia of cephalo preparation (pioneer No. IV, Cefaclor etc.), Indole-positive proteus, Enterobacter, citric acid Pseudomonas etc. show good antibacterial action.Cefteram pivoxil is to various Bacteriogenic beta-lactamase is stablized, therefore the bacterial strain to producing beta-lactamase is effective.
Cefteram pivoxil (also referred to as " Cefteram Pivoxil ") belongs to cephalosporins, and chemical name is (6R, 7R) -7- [(Z) -2- (2- amino -4- thiazolyls) -2- (methoxyimino) acetylamino] -3- [2- (5- methyl -2H- four Azoles -2- bases) methyl) -8- oxos -5- thia -1- azabicyclos [4,2,0] oct-2-ene -2- carboxylic acid pivaloyl oxygen methyl esters, molecule Formula：C22H27N9O7S2, molecular weight：593.64 structure is：
Cefteram pivoxil is insoluble in water, and dissolution is slow.The infiltration rate of the drug in vivo usually speed by dissolving And determine, the drug in solid pharmaceutical preparation is before being absorbed, it is necessary to the process of solution is then turned to by disintegration and dissolving.If medicine Object is not easy to release from preparation or the solution rate of drug is extremely slow, then in said preparation drug infiltration rate or degree It is possible to that there are problems.Cefteram pivoxil is insoluble in water, meets acid and easily decomposes, this leverages the result of extraction of drug And bioavilability.
It can be aoxidized simultaneously in cefteram pivoxil molecule also there are primary amine groups due to Maillard reaction；It is deposited in molecule Photo and thermal stability is preferable under ester bond, amido bond and lactam bond, solid-state, but unstable in solution, meets acid, alkali divides rapidly Solution.Therefore to damp and hot unstable, degradation impurity is easily decomposed to form.
Finally, cefteram pivoxil bulk pharmaceutical chemicals bitter, as directly oral preparation, patient's compliance is poor.
At present, the common formulations of cynnematin esters drug have tablet, capsule and granule etc., preparation method have dry method or Wet granulation, then tabletting, capsule charge or conduct granule use, and also have the correlative study of direct powder compression.Wet granulation It needs to add in wetting agent water or alcohol in the process, easily causes gelation, bonding phenomenon is serious.Direct powder compression effect is poor, is This generally requires the substantial amounts of filler of addition, and to the more demanding of filler, this greatly improves manufacturing cost, and drug is molten Go out bad.Although dry granulation can avoid the gelation problems of wet granulation, gained particle can be used for preparing tablet, capsule or Granule, is the emphasis of Recent study, but always exist meet during medication it is aqueous gelled and the problem of dissolution rate is caused to decline.
Therefore the current urgent problem to be solved of cefteram pivoxil oral solid formulation is to provide a kind of while takes into account primary Amido, ester bond are that amido bond and lactam bond are stablized, dissolution rate is high, effectively cover bitter taste, formula and simple for process and suitable for work The cefteram pivoxil pharmaceutical composition of industry metaplasia production.
The content of the invention
As described above, cefteram pivoxil meet water become sticky, the dissolubility so as to cause cefteram pivoxil it is very low and It is difficult to absorb, i.e., bioavilability is low.Meanwhile cefteram pivoxil has bitter taste, the taste is lasting and cannot pass through addition Simple sweetener, corrigent cover its bitter taste, and finally the drug is unstable in wet, thermal environment, ester bond, and amido bond is easy It disconnects, the easy open loop of lactam nucleus, primary amine groups easily aoxidize.
Inventor has obtained a kind of pharmaceutical composition containing cefteram pivoxil, the combination by further investigation design Object is prepared into oral solid formulation by certain technique.
The pharmaceutical composition containing cefteram pivoxil, by main ingredient cefteram pivoxil, gel inhibitor collapses Solve agent, glidant, lubricant, filler composition.Oral solid formulation is further prepared into as follows：
1) cefteram pivoxil bulk pharmaceutical chemicals is taken to crush, cross 200 mesh sieves, it is spare；
2) filler is taken, partial disintegration agent is sieved for subsequent use；
3) recipe quantity cefteram pivoxil, filler and partial disintegration agent are taken, is uniformly mixed, dry granulation, and whole grain, it must carry Medicine cefteram pivoxil particle；
4) take and carry medicine cefteram pivoxil particle, remaining disintegrant and gel inhibitor, glidant, lubricant is uniformly mixed Obtain preparation intermediate；
In the pharmaceutical composition containing cefteram pivoxil, gel inhibitor is sodium propionate, dosage 4%-8%.
The filler is mannitol.
The glidant is colloidal silicon dioxide.
The lubricant is magnesium stearate.
The disintegrant is low-substituted hydroxypropyl cellulose.
The pharmaceutical composition containing cefteram pivoxil, unit formulation composition are as follows：
The pharmaceutical composition containing cefteram pivoxil, unit formulation composition are as follows：
The pharmaceutical composition containing cefteram pivoxil, preparation process are as follows：
1) cefteram pivoxil bulk pharmaceutical chemicals is taken to crush, cross 200 mesh sieves, it is spare；
2) filler mannitol is taken, 50% recipe quantity disintegrant low-substituted hydroxypropyl cellulose sieves for subsequent use；
3) recipe quantity cefteram pivoxil, filler mannitol and 50% recipe quantity disintegrant low-substituted hydroxypropyl cellulose are taken, It is uniformly mixed, dry granulation, and whole grain, medicine cefteram pivoxil particle must be carried；
4) take and carry medicine cefteram pivoxil particle, remaining 50% recipe quantity disintegrant low-substituted hydroxypropyl cellulose, gel inhibits Agent sodium propionate, glidant colloidal silicon dioxide, magnesium stearate lubricant are uniformly mixed, obtain the medicine containing cefteram pivoxil Compositions.
The foregoing pharmaceutical composition containing cefteram pivoxil can be further prepared into common by film coating Stomach dissolution type film coating tablet.
It can be fitted into the capsule shells of appropriate model, be prepared into hard capsule.
Or appropriate corrigent Aspartame is further added in, mixing is prepared into granule.
Patent application is further illustrated the present invention by testing as follows：
Inventor chances on the aqueous solution of sodium propionate, for head in the research process to cefteram pivoxil bulk pharmaceutical chemicals The generation of spore spy's logical sequence peopentyl ester gel is found there are inhibitory action, after solid sodium propionate and cefteram pivoxil mixing, Gelatinization is equally suppressed.Finally by a series of experiments, it was demonstrated that the sodium propionate of certain dosage is new with Cefteram is inhibited Pentyl ester meets the effect that water forms gel.Again due to containing ester bond, amido bond and lactam bond in cefteram pivoxil structure, hold Facile hydrolysis, thus it is overall using dry granulation process, that is, it solves Flow of Goods and Materials sex chromosome mosaicism, and largely avoids in preparation The hydrolysis of bulk pharmaceutical chemicals, for the bitterness problem of cefteram pivoxil, tablet is solved by being coated, and capsule passes through capsule shells solution Certainly, for particle, then consider to add in Aspartame as corrigent and sodium propionate use in conjunction, experiment proves, works well.
Experiment one：Auxiliary material compatibility test
By cefteram pivoxil bulk pharmaceutical chemicals；Cefteram pivoxil bulk pharmaceutical chemicals respectively with filler low moisture microcrystalline cellulose, Mannitol, disintegrant low-substituted hydroxypropyl cellulose, crospovidone, according to weight ratio 1:5, it is uniformly mixed, Cefteram new penta Ester bulk pharmaceutical chemicals respectively with magnesium stearate lubricant, glidant colloidal silicon dioxide, gel inhibitor sodium propionate, common stomach dissolution type bag Clothing agent Opadry, corrigent Aspartame is by weight 20:1, be uniformly mixed, put respectively in culture dish stand into<Thick thin of 5mm Layer.Sample number into spectrum is respectively A, B, C, D, E, F, G, H, I, J.
Above-mentioned sample is put 60 DEG C respectively, RH20% ± 5%；Illumination 4500Lx ± 500Lx, RH20% ± 5%；Strong striation It places 10 days under part, was sampled in the 5th day and the 10th day, detect cefteram pivoxil content and related substance.Detect data such as Shown in following table.
1 cefteram pivoxil bulk pharmaceutical chemicals of table and auxiliary material compatibility experiments result (60 DEG C, RH20% ± 5%) to be selected
2 cefteram pivoxil bulk pharmaceutical chemicals of table and auxiliary material compatibility experiments result to be selected (strong light 4500Lx ± 500Lx, RH20% ± 5%)
Selected auxiliary material is can be seen that with bulk pharmaceutical chemicals cefteram pivoxil in RH20% ± 5% from more than experimental result Pass through 60 DEG C of high temperature under part, stored under intense light conditions, compared with cefteram pivoxil bulk pharmaceutical chemicals, no significant change.That is cephalo Special logical sequence peopentyl ester and filler low moisture microcrystalline cellulose, mannitol, disintegrant low-substituted hydroxypropyl cellulose, crospovidone, Magnesium stearate lubricant and gel inhibitor sodium propionate, corrigent Aspartame, film coating agent Opadry compatibility is good, Conjunction object can be grouped under solid states with above-mentioned auxiliary material, and be further prepared into solid pharmaceutical preparation, but it is same from experimental result Sample finds out that low-substituted hydroxypropyl cellulose is better than crospovidone, and reason is containing a small amount of peroxide in crospovidone Cefteram pivoxil primary amine groups can be caused to aoxidize, so as to reduce content, and in low-substituted hydroxypropyl cellulose and do not contain peroxide Compound, for the result of the test of similary mannitol due to low moisture microcrystalline cellulose, reason is that mannitol water content is less than low water Divide microcrystalline cellulose, reduce degradation of the moisture to cefteram pivoxil.
Experiment two：Prescription screening tests (tablet, capsule, particle)
Design following prescription：
Above-mentioned prescription purpose is that detect material fluidity, compressibility and sodium propionate dosage meets for cefteram pivoxil The effects that gel after water inhibits.Therefore Cotton seeds are not done to tablet.
Preparation process：
1) cefteram pivoxil bulk pharmaceutical chemicals is taken to crush, cross 200 mesh sieves, it is spare；
2) filler mannitol is taken, 50% recipe quantity disintegrant low-substituted hydroxypropyl cellulose sieves for subsequent use；
3) recipe quantity cefteram pivoxil, filler mannitol and 50% recipe quantity disintegrant low-substituted hydroxypropyl cellulose are taken, It is uniformly mixed, dry granulation, and whole grain, medicine cefteram pivoxil particle must be carried；
4) take and carry medicine cefteram pivoxil particle, remaining 50% recipe quantity disintegrant low-substituted hydroxypropyl cellulose, gel inhibits Agent sodium propionate, glidant colloidal silicon dioxide, magnesium stearate lubricant are uniformly mixed, obtain the medicine containing cefteram pivoxil Compositions；
5) pharmaceutical composition obtained by step 4) is taken, 1/3rd materials results obtain cefteram pivoxil plain piece, 1/3rd objects Material is packed into appropriate model capsule, is hard capsule；
6) surplus material adds in 1.5% Aspartame, and mixing, it in aluminium foil bag, is granule to be fitted into.
Disintegration experiment：
It presses《Chinese Pharmacopoeia》Two annex XA disintegration time limited inspection techniques, metal branch is hung on by hanging basket by the stainless steel shaft of upper end It on frame, immerses in 1000ml beakers, and adjusts when hanging basket position makes its decline sieve away from beaker bottom 25mm, temperature is filled in beaker It spends for the water of 37 DEG C of 0.5 DEG C of scholars, adjusts when height of water level rises hanging basket sieve at the 15mm of underwater.
Above-mentioned 3 test sample of prescription 1- prescriptions 6 is taken respectively, and prescription 1- prescriptions 3 test sample, 6 hard shell capsules are put above-mentioned respectively In the glass tube of hanging basket, start disintegration tester and carry out inspection Check, record a sample disintegration time, it is as shown in the table：
The plain piece sample disintegration experiment (unit of 33 prescriptions of table：Second)
It can be seen from the results above that prescription 2 is similar with the sample average disintegration time of prescription 3, it is 1min or so, and 1 disintegration time of prescription is slightly long, is 1.5 minutes.But this three prescriptions met in Chinese Pharmacopoeia two on the disintegration of tablet time limit Regulation.
2 disintegration time of prescription is waited, based on this as a result, initial option prescription 2 is tablet and capsule best prescription.
Since granule sheet is as the particle of good fluidity, without disintegration, you can absorb, therefore be not suitable for this experiment. But it is granule best prescription equally to take prescription 2.
Experiment three：Bitter taste detects
It is plain piece with above-mentioned prescription 2, with film coating agent Opadry film coating, weightening is respectively 4%-8%.3 prescriptions point 6 coating tablets pieces are not taken, separately take capsule 6, and 6 bags of granule (is disperseed) with appropriate warm water, and 15s, simulation are sucked with 6 volunteers As a result drug oral process records as follows：
The different coating weight gain prescription bitter taste test results of 43, table
It can be seen from the results above that bitter taste is not shown after coating.That is coating weight gain 4-8% can cover plain piece The problem of bitter.
In addition capsule due to there is the inhibition of capsule shells, does not show bitter taste；
For granule, to be dispersed in warm water, subject sucks warm water, and drug and subject oral cavity contact directly, but by In the addition of sodium propionate and corrigent Aspartame, the bitter taste of drug is equally masked.
By this experiment, it is optimal prescription to determine prescription 2.
Experiment four：Dissolution rate test experience
By above-mentioned screening, it is determined that the prescription of the Cefteram Pivoxil Tablets agent of a specification (50mg), capsule and particle and This specification prescription is amplified 2 times and obtains following prescription by preparation process：
The pharmaceutical composition containing cefteram pivoxil, is further prepared into thin membrane coated tablet as follows Agent：1) cefteram pivoxil bulk pharmaceutical chemicals is taken to crush, cross 200 mesh sieves, it is spare；
2) filler mannitol is taken, 50% recipe quantity disintegrant low-substituted hydroxypropyl cellulose sieves for subsequent use；
3) recipe quantity cefteram pivoxil, filler mannitol and 50% recipe quantity disintegrant low-substituted hydroxypropyl cellulose are taken, It is uniformly mixed, dry granulation, and whole grain, medicine cefteram pivoxil particle must be carried；
4) take and carry medicine cefteram pivoxil particle, remaining 50% recipe quantity disintegrant low-substituted hydroxypropyl cellulose, gel inhibits Agent sodium propionate, glidant colloidal silicon dioxide, magnesium stearate lubricant are uniformly mixed, tabletting, obtain cefteram pivoxil element Piece；5) cefteram pivoxil plain piece is taken, is coated with coating agent Opadry, coating weight gain 6% obtains cefteram pivoxil Thin membrane coated tablet.
Capsule prescription is as follows：
Preparation process is as follows：
1) cefteram pivoxil bulk pharmaceutical chemicals is taken to crush, cross 200 mesh sieves, it is spare；
2) filler mannitol is taken, 50% recipe quantity disintegrant low-substituted hydroxypropyl cellulose sieves for subsequent use；
3) recipe quantity cefteram pivoxil, filler mannitol and 50% recipe quantity disintegrant low-substituted hydroxypropyl cellulose are taken, It is uniformly mixed, dry granulation, and whole grain, medicine cefteram pivoxil particle must be carried；
4) take and carry medicine cefteram pivoxil particle, remaining 50% recipe quantity disintegrant low-substituted hydroxypropyl cellulose, gel inhibits Agent sodium propionate, glidant colloidal silicon dioxide, magnesium stearate lubricant are uniformly mixed, obtain the medicine containing cefteram pivoxil Compositions；
5) pharmaceutical composition of cefteram pivoxil obtained by step 4) is taken, is packed by unit capsule content weight suitable for gelatin It is cefteram pivoxil hard capsule in capsule shells.
Granule prescription is as follows：
Preparation process is as follows：
1) cefteram pivoxil bulk pharmaceutical chemicals is taken to crush, cross 200 mesh sieves, it is spare；
2) filler mannitol is taken, 50% recipe quantity disintegrant low-substituted hydroxypropyl cellulose sieves for subsequent use；
3) recipe quantity cefteram pivoxil, filler mannitol and 50% recipe quantity disintegrant low-substituted hydroxypropyl cellulose are taken, It is uniformly mixed, dry granulation, and whole grain, medicine cefteram pivoxil particle must be carried；
4) take and carry medicine cefteram pivoxil particle, remaining 50% recipe quantity disintegrant low-substituted hydroxypropyl cellulose, gel inhibits Agent sodium propionate, glidant colloidal silicon dioxide, corrigent Aspartame, magnesium stearate lubricant are uniformly mixed, must contain cephalo The pharmaceutical composition of special logical sequence peopentyl ester；
5) pharmaceutical composition of cefteram pivoxil obtained by step 4) is taken, is packed by unit grain weight of formulation suitable for volume In aluminium foil bag, cefteram pivoxil granule is obtained.
Dissolution of Tablet test experience：
1,2 specification film coating tablets of Example and Qilu Pharmaceutical Co., Ltd.'s production 50mg marketed tablets three groups of samples point Not number A-C, every group takes 6 samples, presses《Pharmacopeia of Japan》17th edition, dissolution determination under Cefteram Pivoxil Tablets item Method), by paddle method, using purified water 900ml as dissolution medium, rotating speed is 75 turns per minute, is operated in accordance with the law, during through 30 minutes, is taken molten Appropriate liquid, filtration, precision measurement subsequent filtrate is appropriate, is quantitatively diluted and is made new containing about Cefteram penta in every lml with dissolution medium The solution of 20 μ g of ester measures absorbance at the wavelength of 300nm, and it is appropriate that another precision weighs cefteram pivoxil reference substance, adds Dissolution medium, which dissolves and quantifies dilution, to be made in every lml containing about the solution of 20 μ g of cefteram pivoxil, is measured in the same method.It calculates The stripping quantity of every.As a result it is as follows：
5 embodiment of table, 1 tablet (unit compared with marketed tablet sample dissolved corrosion：%)
Sample A B C
Piece 1 92.93 99.74 80.48
Piece 2 99.31 98.37 76.37
Piece 3 90.85 90.41 79.84
Piece 4 98.91 94.27 76.70
Piece 5 97.20 98.46 82.82
Piece 6 97.88 94.76 82.54
Average 96.18 96.00 79.79
.(standard is more than 75%).
It can be seen from the results above that 2 specification Cefteram Pivoxil Tablets agent that the embodiment of the present invention 1 provides, with city It sells tablet to compare, 30min dissolution rates, which have, to be greatly enhanced, and specific data are as shown above.
Capsule dissolution rate test experience：
2,2 specification capsules of Example and Guangdong Bozhou Pharmaceutical Co., Ltd.'s production 50mg commercially available three groups of samples of capsule point Not number A-C, every group takes 6 samples, and by paddle method, using purified water 900ml as dissolution medium, rotating speed is 75 turns per minute, in accordance with the law Operation during through 45 minutes, takes solution appropriate, filters, and it is appropriate that precision measures subsequent filtrate, quantitatively diluted with dissolution medium be made it is every Containing about the solution of 20 μ g of cefteram pivoxil in lml, absorbance is measured at the wavelength of 300nm, another precision weighs cephalo spy Logical sequence peopentyl ester reference substance is appropriate, dissolution medium is added to dissolve and quantifies dilution is made in every lml containing about 20 μ g of cefteram pivoxil Solution, be measured in the same method.Calculate the stripping quantity of every.As a result it is as follows：
6 embodiment of table, 2 capsule (unit compared with commercially available capsule sample dissolved corrosion：%)
Sample A B C
Capsule 1 94.42 94.78 79.54
Capsule 2 98.03 91.50 81.55
Capsule 3 94.44 99.58 79.10
Capsule 4 93.21 97.15 81.57
Capsule 5 97.96 90.85 83.11
Capsule 6 98.05 95.97 84.13
Average 96.02 94.97 81.50
.(standard is more than 75%).
It can be seen from the results above that 2 specification cefteram pivoxil capsules that the embodiment of the present invention 2 provides, with Commercially available capsule is compared, and 45min dissolution rates, which have, to be greatly enhanced, and specific data are as shown above.
Granule dissolution rate test experience：
3,2 specification granules of Example and Simcere Pharmaceutical Co., Ltd.'s production 50mg commercially available dry suspensoid agent (same particles of dosage form Agent) three groups of samples number A-C respectively, every group takes 6 bags of samples, and by paddle method, using purified water 900ml as dissolution medium, rotating speed is every It minutes 75 turns, operates in accordance with the law, during through 30 minutes, takes solution appropriate, filter, it is appropriate that precision measures subsequent filtrate, is determined with dissolution medium Amount dilution is made in every lml containing about the solution of 20 μ g of cefteram pivoxil, and absorbance, another essence are measured at the wavelength of 300nm The close cefteram pivoxil reference substance that weighs is appropriate, dissolution medium is added to dissolve and quantify dilution be made in every lml it is special containing about cephalo The solution of 20 μ g of logical sequence peopentyl ester, is measured in the same method.Calculate the stripping quantity of every.As a result it is as follows：
7 embodiment of table, 3 granule (unit compared with commercial particulate agent sample dissolved corrosion：%)
Sample A B C
Particle 1 95.61 98.01 76.10
Particle 2 92.71 93.43 84.10
Particle 3 98.08 98.26 83.63
Particle 4 99.90 92.63 75.73
Particle 5 98.49 99.42 75.08
Particle 6 96.74 93.90 78.21
Average 96.92 95.94 78.81
(standard is more than 75%).
It can be seen from the results above that 2 specification cefteram pivoxil granules that the embodiment of the present invention 3 provides, with Commercially available dry suspensoid agent (granule) is compared, and 30min dissolution rates, which have, to be greatly enhanced, and specific data are as shown above.
Experiment five：Accelerated stability experiment in 12 months.
Take above-mentioned 2 specification film coating tablets, capsule, granule (embodiment 1-3) and the corresponding city of dissolution test Tablet is sold, capsule, number A-I puts 40 DEG C ± 2 DEG C to nine groups of samples of granule sample respectively respectively successively, 75% ± 5%RH items It is stored 12 months under part, respectively at 0 month, relevant nature is measured by sampling, obtains corresponding data December in June in March in January, it is as follows Shown in table：
8 embodiment 1-3 of table is compared with commercial samples stability
It is special according to prescription described in embodiment 1-3 of the present invention and the cephalo prepared by technique it can be seen from upper table data Logical sequence peopentyl ester tablet, hard capsule and granule, at 40 DEG C ± 2 DEG C, under 75% ± 5%RH acceleration environments, after storage in 12 months, Its content, related substance are varied from, but content, more than 98.5%, maximum list impurity is less than 0.2%, and total impurities is low In 1.0%, tablet 30min dissolution rates are more than 92%, and capsule 45min dissolution rates are more than 92%, and granule 30min dissolution rates are more than 92%；It corresponds, after accelerating storage in 12 months, content is fallen to approximately commercially available cefteram pivoxil preparation 95%, maximum list impurity rises to about 0.5%, and total impurities is then more than 3.0%, and tablet 30min dissolution rates are about 79%, capsule 45min dissolution rates are about 75%, and granule 30min dissolution rates are about 79%.
Based on as above analyzing, according to prescription described in embodiment 1-3 of the present invention and the Cefteram new penta prepared by technique Under acceleration conditions, the data after storing 12 months are shown for ester tablet, hard capsule and granule, and stability is significantly better than city Preparation is sold, i.e., the stability of Cefteram Pivoxil Tablets agent is remarkably reinforced by the prescription and technique of the present invention, it is molten Go out speed and degree has and is obviously improved, so that the present invention has prominent substantive distinguishing features and marked improvement, and have Practicability.
Specific embodiment
The advantageous effect further illustrated the present invention is tested by following.But it is not limited to following embodiments, this field Technical staff made on the basis of the present invention, equivalent substitute or the conversion of substantive content of the present invention are not departed from, also at this Within the protection domain of invention.
1 cefteram pivoxil thin membrane coated tablet of embodiment prepares (unit：g)
Prescription：
Preparation process is as follows：
1) cefteram pivoxil bulk pharmaceutical chemicals is taken to crush, cross 200 mesh sieves, it is spare；
2) filler mannitol is taken, 50% recipe quantity disintegrant low-substituted hydroxypropyl cellulose sieves for subsequent use；
3) recipe quantity cefteram pivoxil, filler mannitol and 50% recipe quantity disintegrant low-substituted hydroxypropyl cellulose are taken, It is uniformly mixed, dry granulation, and whole grain, medicine cefteram pivoxil particle must be carried；
4) take and carry medicine cefteram pivoxil particle, remaining 50% recipe quantity disintegrant low-substituted hydroxypropyl cellulose, gel inhibits Agent sodium propionate, glidant colloidal silicon dioxide, magnesium stearate lubricant are uniformly mixed, obtain the medicine containing cefteram pivoxil Compositions；
5) pharmaceutical composition of cefteram pivoxil obtained by step 4) is taken, tabletting is cefteram pivoxil plain piece；
6) cefteram pivoxil plain piece is taken, is coated with common stomach dissolution type coating agent Opadry, coating weight gain 6% obtains head Spore spy's logical sequence peopentyl ester thin membrane coated tablet.
2 cefteram pivoxil hard capsule of embodiment prepares (unit：g)
Prescription：
Preparation process is as follows：
1) cefteram pivoxil bulk pharmaceutical chemicals is taken to crush, cross 200 mesh sieves, it is spare；
2) filler mannitol is taken, 50% recipe quantity disintegrant low-substituted hydroxypropyl cellulose sieves for subsequent use；
3) recipe quantity cefteram pivoxil, filler mannitol and 50% recipe quantity disintegrant low-substituted hydroxypropyl cellulose are taken, It is uniformly mixed, dry granulation, and whole grain, medicine cefteram pivoxil particle must be carried；
4) take and carry medicine cefteram pivoxil particle, remaining 50% recipe quantity disintegrant low-substituted hydroxypropyl cellulose, gel inhibits Agent sodium propionate, glidant colloidal silicon dioxide, magnesium stearate lubricant are uniformly mixed, obtain the medicine containing cefteram pivoxil Compositions；
5) pharmaceutical composition of cefteram pivoxil obtained by step 4) is taken, is packed by unit capsule content weight suitable for gelatin It is cefteram pivoxil hard capsule in capsule shells.
3 cefteram pivoxil particle preparation (unit of embodiment：g)
Prescription：
Preparation process is as follows：
1) cefteram pivoxil bulk pharmaceutical chemicals is taken to crush, cross 200 mesh sieves, it is spare；
2) filler mannitol is taken, 50% recipe quantity disintegrant low-substituted hydroxypropyl cellulose sieves for subsequent use；
3) recipe quantity cefteram pivoxil, filler mannitol and 50% recipe quantity disintegrant low-substituted hydroxypropyl cellulose are taken, It is uniformly mixed, dry granulation, and whole grain, medicine cefteram pivoxil particle must be carried；
4) take and carry medicine cefteram pivoxil particle, remaining 50% recipe quantity disintegrant low-substituted hydroxypropyl cellulose, gel inhibits Agent sodium propionate, glidant colloidal silicon dioxide, corrigent Aspartame, magnesium stearate lubricant are uniformly mixed, must contain cephalo The pharmaceutical composition of special logical sequence peopentyl ester；
5) pharmaceutical composition of cefteram pivoxil obtained by step 4) is taken, is packed by unit grain weight of formulation suitable for volume In aluminium foil bag, cefteram pivoxil granule is obtained.

Claims (10)

1. a kind of pharmaceutical composition containing cefteram pivoxil, by main ingredient cefteram pivoxil, gel inhibitor, disintegration Agent low-substituted hydroxypropyl cellulose, glidant colloidal silicon dioxide, magnesium stearate lubricant, filler mannitol composition, by such as Lower step is further prepared into oral solid formulation：
1) cefteram pivoxil bulk pharmaceutical chemicals is taken to crush, cross 200 mesh sieves, it is spare；
2) filler is taken, partial disintegration agent is sieved for subsequent use；
3) recipe quantity cefteram pivoxil, filler and partial disintegration agent are taken, is uniformly mixed, dry granulation, and whole grain, it must carry Medicine cefteram pivoxil particle；
4) take and carry medicine cefteram pivoxil particle, remaining disintegrant and gel inhibitor, glidant, lubricant is uniformly mixed Obtain preparation intermediate；
In the pharmaceutical composition containing cefteram pivoxil, gel inhibitor is sodium propionate, dosage 4%-8%.
2. the pharmaceutical composition containing cefteram pivoxil, prescription are as follows as described in claim 1：
3. the pharmaceutical composition containing cefteram pivoxil, prescription are as follows as described in claim 1：
4. any pharmaceutical composition containing cefteram pivoxil, is prepared by following technique as described in claim 2-3 Tablet：
1) cefteram pivoxil bulk pharmaceutical chemicals is taken to crush, cross 200 mesh sieves, it is spare；
2) filler mannitol is taken, 50% recipe quantity disintegrant low-substituted hydroxypropyl cellulose sieves for subsequent use；
3) recipe quantity cefteram pivoxil, filler mannitol and 50% recipe quantity disintegrant low-substituted hydroxypropyl cellulose are taken, It is uniformly mixed, dry granulation, and whole grain, medicine cefteram pivoxil particle must be carried；
4) take and carry medicine cefteram pivoxil particle, remaining 50% recipe quantity disintegrant low-substituted hydroxypropyl cellulose, gel inhibits Agent sodium propionate, glidant colloidal silicon dioxide, magnesium stearate lubricant are uniformly mixed, obtain the medicine containing cefteram pivoxil Compositions；
5) pharmaceutical composition of cefteram pivoxil obtained by step 4) is taken, tabletting is cefteram pivoxil plain piece；
6) cefteram pivoxil plain piece is taken, is coated with common stomach dissolution type coating agent Opadry, coating weight gain 6% obtains head Spore spy's logical sequence peopentyl ester thin membrane coated tablet.
5. the pharmaceutical composition containing cefteram pivoxil, prescription are as follows as described in claim 1：
6. the pharmaceutical composition containing cefteram pivoxil, prescription are as follows as described in claim 1：
7. any pharmaceutical composition containing cefteram pivoxil, is prepared by following technique as described in claim 5-6 Capsule：
1) cefteram pivoxil bulk pharmaceutical chemicals is taken to crush, cross 200 mesh sieves, it is spare；
2) filler mannitol is taken, 50% recipe quantity disintegrant low-substituted hydroxypropyl cellulose sieves for subsequent use；
3) recipe quantity cefteram pivoxil, filler mannitol and 50% recipe quantity disintegrant low-substituted hydroxypropyl cellulose are taken, It is uniformly mixed, dry granulation, and whole grain, medicine cefteram pivoxil particle must be carried；
4) take and carry medicine cefteram pivoxil particle, remaining 50% recipe quantity disintegrant low-substituted hydroxypropyl cellulose, gel inhibits Agent sodium propionate, glidant colloidal silicon dioxide, magnesium stearate lubricant are uniformly mixed, obtain the medicine containing cefteram pivoxil Compositions；
5) pharmaceutical composition of cefteram pivoxil obtained by step 4) is taken, is packed by unit capsule content weight suitable for gelatin It is cefteram pivoxil hard capsule in capsule shells.
8. the pharmaceutical composition containing cefteram pivoxil, prescription are as follows as described in claim 1：
9. the pharmaceutical composition containing cefteram pivoxil, prescription are as follows as described in claim 1：
10. any pharmaceutical composition containing cefteram pivoxil, is prepared by following technique as described in claim 8-9 Granule：
1) cefteram pivoxil bulk pharmaceutical chemicals is taken to crush, cross 200 mesh sieves, it is spare；
2) filler mannitol is taken, 50% recipe quantity disintegrant low-substituted hydroxypropyl cellulose sieves for subsequent use；
3) recipe quantity cefteram pivoxil, filler mannitol and 50% recipe quantity disintegrant low-substituted hydroxypropyl cellulose are taken, It is uniformly mixed, dry granulation, and whole grain, medicine cefteram pivoxil particle must be carried；
4) take and carry medicine cefteram pivoxil particle, remaining 50% recipe quantity disintegrant low-substituted hydroxypropyl cellulose, gel inhibits Agent sodium propionate, glidant colloidal silicon dioxide, corrigent Aspartame, magnesium stearate lubricant are uniformly mixed, must contain cephalo The pharmaceutical composition of special logical sequence peopentyl ester；
5) pharmaceutical composition of cefteram pivoxil obtained by step 4) is taken, is packed by unit grain weight of formulation suitable for volume In aluminium foil bag, cefteram pivoxil granule is obtained.
CN201810192145.4A 2018-03-08 2018-03-08 A kind of pharmaceutical composition containing cefteram pivoxil Withdrawn CN108113972A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108815129A (en) * 2018-07-12 2018-11-16 天津双硕医药科技有限公司 A kind of miscellaneous Shandong amine nanocrystal oral solid drug composition of grace
CN110934841A (en) * 2019-12-31 2020-03-31 山东罗欣药业集团股份有限公司 Cefteram pivoxil tablet composition

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103845298A (en) * 2014-03-20 2014-06-11 辽宁亿灵科创生物医药科技有限公司 Cefuroxime axetil dispersible tablet
CN104940158A (en) * 2015-06-09 2015-09-30 杨玉廷 Medicine composition containing cefuroxime axetil and preparation method of medicine composition
CN105168164A (en) * 2015-07-29 2015-12-23 董贵雨 Solid medicine composition with moxifloxacin

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103845298A (en) * 2014-03-20 2014-06-11 辽宁亿灵科创生物医药科技有限公司 Cefuroxime axetil dispersible tablet
CN104940158A (en) * 2015-06-09 2015-09-30 杨玉廷 Medicine composition containing cefuroxime axetil and preparation method of medicine composition
CN105168164A (en) * 2015-07-29 2015-12-23 董贵雨 Solid medicine composition with moxifloxacin

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108815129A (en) * 2018-07-12 2018-11-16 天津双硕医药科技有限公司 A kind of miscellaneous Shandong amine nanocrystal oral solid drug composition of grace
CN110934841A (en) * 2019-12-31 2020-03-31 山东罗欣药业集团股份有限公司 Cefteram pivoxil tablet composition

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Application publication date: 20180605