CN108159052A - A kind of pharmaceutical composition containing Cefetamet Pivoxil Hydrochloride - Google Patents

A kind of pharmaceutical composition containing Cefetamet Pivoxil Hydrochloride Download PDF

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CN108159052A
CN108159052A CN201810192134.6A CN201810192134A CN108159052A CN 108159052 A CN108159052 A CN 108159052A CN 201810192134 A CN201810192134 A CN 201810192134A CN 108159052 A CN108159052 A CN 108159052A
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cefetamet pivoxil
pivoxil hydrochloride
pharmaceutical composition
composition containing
cefetamet
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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
    • 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
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • 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
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

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  • Bioinformatics & Cheminformatics (AREA)
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  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
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  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
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  • Molecular Biology (AREA)
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Abstract

The invention discloses a kind of pharmaceutical compositions containing Cefetamet Pivoxil Hydrochloride, it is used as gel inhibitor by adding in sodium cyclamate 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 there is the property of sweet taste using sodium cyclamate, 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 Cefetamet Pivoxil Hydrochloride
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to a kind of pharmaceutical composition containing Cefetamet Pivoxil Hydrochloride and its Preparation method.
Background technology
Cefetamet Pivoxil Hydrochloride (Cefetamet Pivoxil) is oral third generation cephalosporin, through intestinal wall ester after taking orally Enzyme takes off ester and releases the cephalosporin with antibacterial activity, has broad-spectrum antibacterial action to Grain-positive and gram-negative bacteria. Cefetamet Pivoxil Hydrochloride may have microspironema pallidum effect, but there are few effects to anaerobic bacteria.Cefetamet Pivoxil Hydrochloride treatment is exhaled Desorption system, urinary system infection contamination and bacteremic efficient respectively 83.3%, 91.2% and 66.6%.From daily various dose To the clinical curative effect analysis of various diseases, daily administration 500mg or 1000mg is to the effective percentage of acute respiratory infections 92.65% and 91.4%, the effective percentage to pulmonary infection is 71.4% and 93.2%, to the effective percentage of chronic respiratory system infection For 71.9% and 80.4%, show that daily administration 1000mg is preferred.
Cefetamet Pivoxil Hydrochloride is 69.2% to the bacteriology clearance rate of gram positive bacteria, gram-negative bacteria 79.8%, Staphylococcus aureus is 61.1%, pseudomonas aeruginosa 0%.To 193 acute bacterial infections patients using random, right According to, the safety of open clinical laboratory evaluations Cefetamet Pivoxil Hydrochloride and validity.Treatment group 98 take hydrochloric acid cephalo he U.S. ester, 250~500mg every time, 2 times a day, control group 95 take Cefixime, each 200mg, 2 times a day, continuous 7~ 14 days.As a result treated effect is respectively 95% and 94%, and the extremely sensitive percentage of bacterium is 98% and 96%, and bacteriology is removed Rate is 96% and 94%.167 bacterial infection patients are randomly divided into test group 59, control group 56, open group 52, are commented Valency effectiveness and reliability.Cefetamet Pivoxil Hydrochloride is taken by treatment group, and each 400mg, 2 times a day, control group takes cephalo gram Oxime, each 200mg, 2 times a day, continuous 7~14 days.As a result treatment group and control group treatment cure rate be respectively 74.5% and 83.14%, effective percentage is 91.5% and 91.07%, and bacteriology clearance rate is 96% and 95.7%.It opens the cure rate of group and has Efficiency is 80.77% and 92.3%, and bacteriology clearance rate is 100%.Three groups of adverse reaction rate is 8.47%, 8.93% With 5.77%.Cefetamet Pivoxil Hydrochloride up to 91.2%, reaches Skin and soft tissue infection effective percentage urinary tract infections effective percentage 78%, to gynecological infections effective percentage up to 92%~97%, Cefetamet Pivoxil Hydrochloride has broad-spectrum antibacterial action to G+ and G- bacterium, It is especially strong to G- bacterium antibacterial activities.
Cefetamet Pivoxil Hydrochloride (CefetametPivoxil), entitled (6R, 7R) -3- methyl -7- [(Z) -2- (2- of chemistry Amino -4- thiazolyls) -2- (methoxyimino)-acetylamino] -8- oxos -5- thia -1- azabicyclos [4,2,0] octyl- 2- Alkene -2- formic acid pivaloyl oxygen methyl ester hydrochlorides, molecular formula：C20H25N5O7S2HCL, molecular weight 548.04, structural formula is as follows：
Cefetamet Pivoxil Hydrochloride raw material meets water and becomes sticky, and after being made into solid pharmaceutical preparation, meeting water can equally become sticky, so as to hinder The only dissolution of main ingredient ingredient, and then the physiological dispositions such as absorption for influencing drug.
Also there are primary amine groups in Cefetamet Pivoxil Hydrochloride molecule simultaneously, can be aoxidized due to Maillard reaction；It is deposited in molecule In ester bond, amido bond and lactam bond, to damp and hot unstable, it is easily decomposed to form degradation impurity.
Finally, Cefetamet Pivoxil Hydrochloride bulk pharmaceutical chemicals bitter, as directly oral preparation, patient's compliance is poor.
At present, the common formulations of cephalosporin 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 a large amount of filler of addition, and to the more demanding of filler, this greatly improves manufacturing cost, and drug is molten Go out bad.Dry granulation can avoid the gelation problems of wet granulation, and gained particle can be used for preparing tablet, capsule or particle Agent, 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 Cefetamet Pivoxil Hydrochloride 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 Cefetamet Pivoxil Hydrochloride pharmaceutical composition of industry metaplasia production.
Invention content
As described above, Cefetamet Pivoxil Hydrochloride meet water become sticky, the dissolubility so as to cause Cefetamet Pivoxil Hydrochloride it is very low and It is difficult to absorb, i.e., bioavilability is low.Cefetamet Pivoxil Hydrochloride have bitter taste, be unfavorable for children taking, finally the drug it is wet, Unstable in thermal environment, primary amine groups are oxidized easily, and ester bond, amido bond easily disconnects, the easy open loop of lactam nucleus.
Inventor has obtained a kind of pharmaceutical composition containing Cefetamet Pivoxil Hydrochloride, the combination by further investigation design Object is prepared into oral solid formulation by certain technique.
The pharmaceutical composition containing Cefetamet Pivoxil Hydrochloride, by main ingredient Cefetamet Pivoxil Hydrochloride, gel inhibitor collapses Solve agent, lubricant, filler composition.It is further prepared into oral solid formulation as follows：
1) Cefetamet Pivoxil Hydrochloride bulk pharmaceutical chemicals is taken to crush, cross 200 mesh sieve, it is spare；
2) filler is taken, partial disintegration agent is sieved for subsequent use；
3) recipe quantity Cefetamet Pivoxil Hydrochloride, filler and partial disintegration agent are taken, is uniformly mixed, dry granulation, and whole grain, must carry Medicine Cefetamet Pivoxil Hydrochloride particle；
4) it takes and carries medicine Cefetamet Pivoxil Hydrochloride particle, remaining disintegrant and gel inhibitor, lubricant is uniformly mixed to obtain preparation Intermediate.
In the pharmaceutical composition containing Cefetamet Pivoxil Hydrochloride, gel inhibitor is sodium cyclamate, dosage 1%- 5%.
The filler is mannitol.
The lubricant is magnesium stearate.
The disintegrant is low-substituted hydroxypropyl cellulose.
The pharmaceutical composition containing Cefetamet Pivoxil Hydrochloride, unit formulation composition are as follows：
The pharmaceutical composition containing Cefetamet Pivoxil Hydrochloride, unit formulation composition are as follows：
The pharmaceutical composition containing Cefetamet Pivoxil Hydrochloride, preparation process are as follows：
1) Cefetamet Pivoxil Hydrochloride bulk pharmaceutical chemicals is taken to crush, cross 200 mesh sieve, it is spare；
2) filler mannitol is taken, 50% recipe quantity disintegrant low-substituted hydroxypropyl cellulose sieves for subsequent use；
3) recipe quantity Cefetamet Pivoxil Hydrochloride, filler mannitol and 50% recipe quantity disintegrant low-substituted hydroxypropyl cellulose are taken, It is uniformly mixed, dry granulation, and whole grain, medicine Cefetamet Pivoxil Hydrochloride particle must be carried；
4) it takes and carries medicine Cefetamet Pivoxil Hydrochloride particle, remaining 50% recipe quantity disintegrant low-substituted hydroxypropyl cellulose, gel inhibits Agent sodium cyclamate, magnesium stearate lubricant are uniformly mixed, obtain the pharmaceutical composition containing Cefetamet Pivoxil Hydrochloride.
The aforementioned pharmaceutical composition containing Cefetamet Pivoxil Hydrochloride can be further prepared into common by film coating Stomach dissolution type film coating tablet.
It can be fitted into capsule shells or the aluminium foil bag of appropriate model, be prepared into hard capsule or granule.
Patent application is further illustrated the present invention by testing as follows：
Inventor chances on the aqueous solution of sodium cyclamate in the research process to Cefetamet Pivoxil Hydrochloride bulk pharmaceutical chemicals, for The generation of Cefetamet Pivoxil Hydrochloride gel finds that solid sodium cyclamate and Cefetamet Pivoxil Hydrochloride are mixed there are inhibiting effect Afterwards, gelatinization is equally suppressed.Finally by a series of experiments, it was demonstrated that the sodium cyclamate of certain dosage, which has, inhibits hydrochloric acid Cefetamet Pivoxil meets the effect that water forms gel.Again due to containing ester bond, amido bond and interior acyl in Cefetamet Pivoxil Hydrochloride structure Amine key easily hydrolyzes, therefore overall using dry granulation process, that is, solves Flow of Goods and Materials sex chromosome mosaicism, and largely avoid The hydrolysis of bulk pharmaceutical chemicals in preparation, finally since sodium cyclamate has sweet taste in itself, the technique that coordinates dry granulation effectively solves The problem of preparation bitter.
Experiment one：Auxiliary material compatibility test
By Cefetamet Pivoxil Hydrochloride bulk pharmaceutical chemicals；Cefetamet Pivoxil Hydrochloride 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, hydrochloric acid cefetamet Ester bulk pharmaceutical chemicals are respectively with magnesium stearate lubricant, and gel inhibitor sodium cyclamate, common stomach dissolution type coating agent Opadry is by weight Than 20:1, be uniformly mixed, put respectively in culture dish booth into<The thin layer of 5mm thickness.Sample number into spectrum is respectively A, B, C, D, E, F, G, H.
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 Cefetamet Pivoxil Hydrochloride content and related substance.Detection data is such as Shown in following table.
1 Cefetamet Pivoxil Hydrochloride bulk pharmaceutical chemicals of table and auxiliary material compatibility experiments result (60 DEG C, RH20% ± 5%) to be selected
2 Cefetamet Pivoxil Hydrochloride 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 Cefetamet Pivoxil Hydrochloride 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 Cefetamet Pivoxil Hydrochloride bulk pharmaceutical chemicals, no significant change.That is hydrochloric acid Cefetamet Pivoxil and filler low moisture microcrystalline cellulose, mannitol, disintegrant low-substituted hydroxypropyl cellulose, crospovidone, Magnesium stearate lubricant and gel inhibitor sodium cyclamate, film coating agent Opadry compatibility is good, can with it is above-mentioned auxiliary Material is grouped conjunction object, and be further prepared into solid pharmaceutical preparation under solid states, but equally finds out from experimental result, low substitution Hydroxypropylcellulose be better than crospovidone, it is possible the reason of be in crospovidone contain a small amount of peroxide can cause salt The oxidation of sour Cefetamet Pivoxil primary amine groups so as to reduce content, and in low-substituted hydroxypropyl cellulose and does not contain peroxide.
Experiment two：Prescription screening tests (tablet, capsule, particle)
Design following prescription：
Above-mentioned prescription purpose is that detect material fluidity, compressibility and sodium cyclamate meets water for Cefetamet Pivoxil Hydrochloride The effects that gel afterwards inhibits.Therefore Cotton seeds are not done to tablet.
Preparation process：
1) Cefetamet Pivoxil Hydrochloride bulk pharmaceutical chemicals is taken to crush, cross 200 mesh sieve, it is spare；
2) filler mannitol is taken, 50% recipe quantity disintegrant low-substituted hydroxypropyl cellulose sieves for subsequent use；
3) recipe quantity Cefetamet Pivoxil Hydrochloride, filler mannitol and 50% recipe quantity disintegrant low-substituted hydroxypropyl cellulose are taken, It is uniformly mixed, dry granulation, and whole grain, medicine Cefetamet Pivoxil Hydrochloride particle must be carried；
4) it takes and carries medicine Cefetamet Pivoxil Hydrochloride particle, remaining 50% recipe quantity disintegrant low-substituted hydroxypropyl cellulose, gel inhibits Agent sodium cyclamate, magnesium stearate lubricant are uniformly mixed, obtain the pharmaceutical composition containing Cefetamet Pivoxil Hydrochloride；
5) pharmaceutical composition obtained by step 4) is taken, 1/3rd materials results obtain Cefetamet Pivoxil Hydrochloride plain piece, 1/3rd objects Material is reloaded into appropriate model capsule, as hard capsule by unit formulation, and surplus material is reloaded by unit formulation suitable for aluminium foil In bag, as granule.
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 the water for 37 DEG C ± 0.5 DEG C, 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 about the disintegration of tablet time limit Regulation.
The disintegration time of prescription 2 is slightly shorter, 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.
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 are in direct contact, but by In the addition of sodium cyclamate, gel inhibitor is acted not only as, itself is sweetener, therefore equally masks the hardship of drug Taste.
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 cefetamet pivoxil hydrochloride tablets agent of a specification (125mg), capsule and particle and Preparation process, amplifies 2 times by this specification prescription and its respectively, 3 times, 4 times following prescription：
The pharmaceutical composition containing Cefetamet Pivoxil Hydrochloride, is further prepared into thin membrane coated tablet as follows Agent：1) Cefetamet Pivoxil Hydrochloride bulk pharmaceutical chemicals is taken to crush, cross 200 mesh sieve, it is spare；
2) filler mannitol is taken, 50% recipe quantity disintegrant low-substituted hydroxypropyl cellulose sieves for subsequent use；
3) recipe quantity Cefetamet Pivoxil Hydrochloride, filler mannitol and 50% recipe quantity disintegrant low-substituted hydroxypropyl cellulose are taken, It is uniformly mixed, dry granulation, and whole grain, medicine Cefetamet Pivoxil Hydrochloride particle must be carried；
4) it takes and carries medicine Cefetamet Pivoxil Hydrochloride particle, remaining 50% recipe quantity disintegrant low-substituted hydroxypropyl cellulose, gel inhibits Agent sodium cyclamate, magnesium stearate lubricant are uniformly mixed, and tabletting obtains Cefetamet Pivoxil Hydrochloride plain piece；
5) Cefetamet Pivoxil Hydrochloride plain piece is taken, is coated with coating agent Opadry, coating weight gain 6% obtains hydrochloric acid cefetamet Ester film coating tablet.
Capsule prescription is as follows：
Preparation process is as follows：
1) Cefetamet Pivoxil Hydrochloride bulk pharmaceutical chemicals is taken to crush, cross 200 mesh sieve, it is spare；
2) filler mannitol is taken, 50% recipe quantity disintegrant low-substituted hydroxypropyl cellulose sieves for subsequent use；
3) recipe quantity Cefetamet Pivoxil Hydrochloride, filler mannitol and 50% recipe quantity disintegrant low-substituted hydroxypropyl cellulose are taken, It is uniformly mixed, dry granulation, and whole grain, medicine Cefetamet Pivoxil Hydrochloride particle must be carried；
4) it takes and carries medicine Cefetamet Pivoxil Hydrochloride particle, remaining 50% recipe quantity disintegrant low-substituted hydroxypropyl cellulose, gel inhibits Agent sodium cyclamate, magnesium stearate lubricant are uniformly mixed, obtain the pharmaceutical composition containing Cefetamet Pivoxil Hydrochloride；
5) pharmaceutical composition of Cefetamet Pivoxil Hydrochloride obtained by step 4) is taken, is reloaded by unit capsule content suitable for gelatin glue It is Cefetamet Pivoxil Hydrochloride hard capsule in softgel shell.
Granule prescription is as follows：
Preparation process is as follows：
1) Cefetamet Pivoxil Hydrochloride bulk pharmaceutical chemicals is taken to crush, cross 200 mesh sieve, it is spare；
2) filler mannitol is taken, 50% recipe quantity disintegrant low-substituted hydroxypropyl cellulose sieves for subsequent use；
3) recipe quantity Cefetamet Pivoxil Hydrochloride, filler mannitol and 50% recipe quantity disintegrant low-substituted hydroxypropyl cellulose are taken, It is uniformly mixed, dry granulation, and whole grain, medicine Cefetamet Pivoxil Hydrochloride particle must be carried；
4) it takes and carries medicine Cefetamet Pivoxil Hydrochloride particle, remaining 50% recipe quantity disintegrant low-substituted hydroxypropyl cellulose, gel inhibits Agent sodium cyclamate, magnesium stearate lubricant are uniformly mixed, obtain the pharmaceutical composition containing Cefetamet Pivoxil Hydrochloride；
5) pharmaceutical composition of Cefetamet Pivoxil Hydrochloride obtained by step 4) is taken, the aluminium suitable for volume is reloaded by unit formulation particle In foil bag, Cefetamet Pivoxil Hydrochloride granule is obtained.
Dissolution of Tablet test experience：
Example Isosorbide-5-Nitrae specification film coating tablet and Apeloa Kangyu Pharmaceutical Co., Ltd.'s production 250mg marketed tablets Five groups of samples number A-E respectively, every group takes 6 samples, presses《Chinese Pharmacopoeia》Two, dissolution rate under cefetamet pivoxil hydrochloride tablets item Measuring method, by paddle method, using 0.lmol/L hydrochloric acid solutions 900ml as dissolution medium, rotating speed is 75 turns per minute, is operated in accordance with the law, is passed through At 45 minutes, take solution appropriate, filter, precision measure subsequent filtrate it is appropriate, quantitatively diluted with dissolution medium be made in every lml containing about The solution of 10 μ g of cefetamet according to UV-VIS spectrophotometry (general rule 0401), measures absorbance at the wavelength of 263nm, It is appropriate that another precision weighs Cefetamet Pivoxil reference substance, dissolution medium is added to dissolve and quantify dilution be made in every lml containing about cephalo he The solution of 10 μ g of U.S., is measured in the same method.Calculate 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：%)
。
(standard is more than 80%).
It can be seen from the results above that 4 specification cefetamet pivoxil hydrochloride tablets agent that the embodiment of the present invention 1 provides, with Zhejiang The tablet of the abundant pharmaceutical Co. Ltd's productions of river Pu Luokang is compared, and 45min dissolution rates, which have, to be greatly enhanced, specific data such as upper table It is shown.
Capsule dissolution rate test experience：
2,4 specification capsules of Example and Zhejiang Zhenyuan Pharmaceutical Co., Ltd's production commercially available five groups of samples of capsule of 125mg Number A-E respectively, every group takes 6 samples, presses《Chinese Pharmacopoeia》Two, dissolution determination under cefetamet pivoxil hydrochloride capsule item Method, by Rotating shaker, using 0.lmol/L hydrochloric acid solutions 900ml as dissolution medium, rotating speed is 100 turns per minute, is operated in accordance with the law, through 30 It during minute, takes solution appropriate, filters, precision measurement subsequent filtrate is appropriate, is quantitatively diluted and is made in every lml containing about head with dissolution medium The solution of his 10 μ g of U.S. of spore according to UV-VIS spectrophotometry (general rule 0401), measures absorbance, separately at the wavelength of 263mn It is appropriate that precision weighs Cefetamet Pivoxil reference substance, dissolution medium is added to dissolve and quantifies dilution is made in every lml containing about cefetamet The solution of 10 μ g, is 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 D E
Capsule 1 95.26 95.83 98.80 98.50 93.81
Capsule 2 99.58 96.47 97.02 94.38 89.69
Capsule 3 96.21 92.47 92.37 96.62 85.84
Capsule 4 94.89 99.79 93.05 93.13 90.14
Capsule 5 95.87 99.52 94.51 96.36 91.55
Capsule 6 95.57 97.30 93.61 94.30 91.87
Mean value 96.23 96.90 94.89 95.55 90.48
。
(standard is more than 85%).
It can be seen from the results above that 4 specification cefetamet pivoxil hydrochloride capsule agent that the embodiment of the present invention 2 provides, with The capsule of Zhejiang Zhenyuan Pharmaceutical Co., Ltd's production is compared, and 30min dissolution rates, which have, to be greatly enhanced, specific data such as upper table It is shown.
Granule dissolution rate test experience：
(dosage form is same for 3,4 specification granules of Example and the commercially available dry suspensoid agents of Zhejiang Zhenyuan Pharmaceutical Co., Ltd production 125mg Granule) five groups of samples number A-E respectively, every group takes 6 bags of samples, presses《Chinese Pharmacopoeia》Two, Cefetamet Pivoxil Hydrochloride is dry-mixed Dissolution method under suspension item, by paddle method, using 0.1mol/L hydrochloric acid solutions 900ml as dissolution medium, rotating speed is per minute 50 Turn, operate in accordance with the law, during through 30 minutes, take solution appropriate, filter, it is appropriate that precision measures subsequent filtrate, is quantitatively diluted with dissolution medium It is made in every lml containing about the solution of 10 μ g of cefetamet, according to UV-VIS spectrophotometry (general rule 0401), in the wave of 263mn Strong point measures absorbance, and it is appropriate that another precision weighs Cefetamet Pivoxil reference substance, dissolution medium is added to dissolve and quantifies dilution is made often Containing about the solution of 10 μ g of cefetamet in lml, it is measured in the same method.Calculate every bag of stripping quantity.As a result it is as follows：7 embodiment of table 3 Granula (unit compared with commercial particulate agent sample dissolved corrosion：%)
Sample A B C D E
Particle 1 97.50 99.38 91.85 99.94 88.64
Particle 2 99.35 94.04 93.39 94.16 80.42
Particle 3 92.08 95.00 96.96 97.66 89.93
Particle 4 95.00 90.57 97.13 91.62 84.35
Particle 5 92.10 99.12 97.00 94.34 82.63
Particle 6 92.49 96.30 97.56 91.74 83.42
Mean value 94.75 95.74 95.65 94.91 84.90
。
(standard is more than 80%).
It can be seen from the results above that 4 specification Cefetamet Pivoxil Hydrochloride granules that the embodiment of the present invention 3 provides, with The dry suspensoid agent (granule) of Zhejiang Zhenyuan Pharmaceutical Co., Ltd's production is compared, and 30min dissolution rates, which have, to be greatly enhanced, specifically Data are as shown above.
Experiment five：Accelerated stability experiment in 12 months.
Take above-mentioned 4 specification film coating tablets, capsule, granule (embodiment 1-3) and the corresponding city of dissolution test Tablet is sold, capsule, number A-O puts 40 DEG C ± 2 DEG C to 15 groups of samples of granule sample respectively respectively successively, 75% ± 5%RH Under the conditions of store 12 months, respectively at 0 month, in January, in March, in June, December was measured by sampling relevant nature, obtains corresponding data, such as Shown in following table：
8 embodiment 1-3 of table is compared with commercial samples stability
According to prescription described in embodiment 1-3 of the present invention and the hydrochloric acid head prepared by technique it can be seen from upper table data His U.S. ester tablet of spore, 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 are low In 1.0%, tablet 45min dissolution rates are more than 92%, and capsule 30min dissolution rates are about 92%, and particle 30min dissolution rates are more than 92%；It corresponds, after accelerating storage in 12 months, content is fallen to approximately for commercially available Cefetamet Pivoxil Hydrochloride preparation agent 95%, maximum list impurity rises to about 0.5%, and total impurities are then more than 2.2%, and tablet 45min dissolution rates are about 85%, capsule 30min dissolution rates are about 85%, and particle 30min dissolution rates are about 82%.
Based on as above analyzing, according to prescription described in embodiment 1-3 of the present invention and the hydrochloric acid cefetamet 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 cefetamet pivoxil hydrochloride 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, while the bitter taste of granule is improved, so that the present invention has prominent reality Matter feature and marked improvement, and with 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 transformation of substantive content of the present invention are not departed from, also at this Within the protection domain of invention.
1 Cefetamet Pivoxil Hydrochloride thin membrane coated tablet of embodiment prepares (unit：g)
Prescription：
Preparation process is as follows：
1) Cefetamet Pivoxil Hydrochloride bulk pharmaceutical chemicals is taken to crush, cross 200 mesh sieve, it is spare；
2) filler mannitol is taken, 50% recipe quantity disintegrant low-substituted hydroxypropyl cellulose sieves for subsequent use；
3) recipe quantity Cefetamet Pivoxil Hydrochloride, filler mannitol and 50% recipe quantity disintegrant low-substituted hydroxypropyl cellulose are taken, It is uniformly mixed, dry granulation, and whole grain, medicine Cefetamet Pivoxil Hydrochloride particle must be carried；
4) it takes and carries medicine Cefetamet Pivoxil Hydrochloride particle, remaining 50% recipe quantity disintegrant low-substituted hydroxypropyl cellulose, gel inhibits Agent sodium cyclamate, magnesium stearate lubricant are uniformly mixed, obtain the pharmaceutical composition containing Cefetamet Pivoxil Hydrochloride；
5) pharmaceutical composition of Cefetamet Pivoxil Hydrochloride obtained by step 4) is taken, tabletting is Cefetamet Pivoxil Hydrochloride plain piece；
6) Cefetamet Pivoxil Hydrochloride plain piece is taken, is coated with common stomach dissolution type coating agent Opadry, coating weight gain 6% obtains salt Sour Cefetamet Pivoxil thin membrane coated tablet.
2 Cefetamet Pivoxil Hydrochloride hard capsule of embodiment prepares (unit：g)
Prescription：
Preparation process is as follows：
1) Cefetamet Pivoxil Hydrochloride bulk pharmaceutical chemicals is taken to crush, cross 200 mesh sieve, it is spare；
2) filler mannitol is taken, 50% recipe quantity disintegrant low-substituted hydroxypropyl cellulose sieves for subsequent use；
3) recipe quantity Cefetamet Pivoxil Hydrochloride, filler mannitol and 50% recipe quantity disintegrant low-substituted hydroxypropyl cellulose are taken, It is uniformly mixed, dry granulation, and whole grain, medicine Cefetamet Pivoxil Hydrochloride particle must be carried；
4) it takes and carries medicine Cefetamet Pivoxil Hydrochloride particle, remaining 50% recipe quantity disintegrant low-substituted hydroxypropyl cellulose, gel inhibits Agent sodium cyclamate, magnesium stearate lubricant are uniformly mixed, obtain the pharmaceutical composition containing Cefetamet Pivoxil Hydrochloride；
5) pharmaceutical composition of Cefetamet Pivoxil Hydrochloride obtained by step 4) is taken, is packed by unit capsule content weight suitable for gelatin It is Cefetamet Pivoxil Hydrochloride hard capsule in capsule shells.
3 Cefetamet Pivoxil Hydrochloride particle preparation (unit of embodiment：g)
Prescription：
Preparation process is as follows：
1) Cefetamet Pivoxil Hydrochloride bulk pharmaceutical chemicals is taken to crush, cross 200 mesh sieve, it is spare；
2) filler mannitol is taken, 50% recipe quantity disintegrant low-substituted hydroxypropyl cellulose sieves for subsequent use；
3) recipe quantity Cefetamet Pivoxil Hydrochloride, filler mannitol and 50% recipe quantity disintegrant low-substituted hydroxypropyl cellulose are taken, It is uniformly mixed, dry granulation, and whole grain, medicine Cefetamet Pivoxil Hydrochloride particle must be carried；
4) it takes and carries medicine Cefetamet Pivoxil Hydrochloride particle, remaining 50% recipe quantity disintegrant low-substituted hydroxypropyl cellulose, gel inhibits Agent sodium cyclamate, magnesium stearate lubricant are uniformly mixed, obtain the pharmaceutical composition containing Cefetamet Pivoxil Hydrochloride；
5) pharmaceutical composition of Cefetamet Pivoxil Hydrochloride obtained by step 4) is taken, is packed by unit grain weight of formulation suitable for volume In aluminium foil bag, Cefetamet Pivoxil Hydrochloride granule is obtained.

Claims (10)

1. a kind of pharmaceutical composition containing Cefetamet Pivoxil Hydrochloride, composition are as follows：
2. a kind of pharmaceutical composition containing Cefetamet Pivoxil Hydrochloride, composition are as follows：
3. a kind of pharmaceutical composition containing Cefetamet Pivoxil Hydrochloride, composition are as follows：
4. a kind of pharmaceutical composition containing Cefetamet Pivoxil Hydrochloride, composition are as follows：
5. any pharmaceutical composition containing Cefetamet Pivoxil Hydrochloride, is prepared by following technique as described in claim 1-4 Tablet：
1) Cefetamet Pivoxil Hydrochloride bulk pharmaceutical chemicals is taken to crush, cross 200 mesh sieve, it is spare；
2) filler mannitol is taken, 50% recipe quantity disintegrant low-substituted hydroxypropyl cellulose sieves for subsequent use；
3) recipe quantity Cefetamet Pivoxil Hydrochloride, filler mannitol and 50% recipe quantity disintegrant low-substituted hydroxypropyl cellulose are taken, It is uniformly mixed, dry granulation, and whole grain, medicine Cefetamet Pivoxil Hydrochloride particle must be carried；
4) it takes and carries medicine Cefetamet Pivoxil Hydrochloride particle, remaining 50% recipe quantity disintegrant low-substituted hydroxypropyl cellulose, gel inhibits Agent sodium cyclamate, magnesium stearate lubricant are uniformly mixed, obtain the pharmaceutical composition containing Cefetamet Pivoxil Hydrochloride；
5) pharmaceutical composition of Cefetamet Pivoxil Hydrochloride obtained by step 4) is taken, tabletting is Cefetamet Pivoxil Hydrochloride plain piece；
6) Cefetamet Pivoxil Hydrochloride plain piece is taken, is coated with common stomach dissolution type coating agent Opadry, coating weight gain 6% obtains salt Sour Cefetamet Pivoxil thin membrane coated tablet.
6. a kind of pharmaceutical composition containing Cefetamet Pivoxil Hydrochloride, composition are as follows：
7. a kind of pharmaceutical composition containing Cefetamet Pivoxil Hydrochloride, composition are as follows：
8. a kind of pharmaceutical composition containing Cefetamet Pivoxil Hydrochloride, composition are as follows：
9. a kind of pharmaceutical composition containing Cefetamet Pivoxil Hydrochloride, composition are as follows：
10. any pharmaceutical composition containing Cefetamet Pivoxil Hydrochloride, is prepared by following technique as described in claim 6-9 Capsule：
1) Cefetamet Pivoxil Hydrochloride bulk pharmaceutical chemicals is taken to crush, cross 200 mesh sieve, it is spare；
2) filler mannitol is taken, 50% recipe quantity disintegrant low-substituted hydroxypropyl cellulose sieves for subsequent use；
3) recipe quantity Cefetamet Pivoxil Hydrochloride, filler mannitol and 50% recipe quantity disintegrant low-substituted hydroxypropyl cellulose are taken, It is uniformly mixed, dry granulation, and whole grain, medicine Cefetamet Pivoxil Hydrochloride particle must be carried；
4) it takes and carries medicine Cefetamet Pivoxil Hydrochloride particle, remaining 50% recipe quantity disintegrant low-substituted hydroxypropyl cellulose, gel inhibits Agent sodium cyclamate, magnesium stearate lubricant are uniformly mixed, obtain the pharmaceutical composition containing Cefetamet Pivoxil Hydrochloride；
5) pharmaceutical composition of Cefetamet Pivoxil Hydrochloride obtained by step 4) is taken, is packed by unit capsule content weight suitable for gelatin It is Cefetamet Pivoxil Hydrochloride hard capsule in capsule shells.
CN201810192134.6A 2018-03-08 2018-03-08 A kind of pharmaceutical composition containing Cefetamet Pivoxil Hydrochloride Withdrawn CN108159052A (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104800221A (en) * 2015-05-15 2015-07-29 苗怡文 Medicinal cefetamet pivoxil hydrochloride composition for treating sensitive bacteria infectious diseases
CN104876947A (en) * 2015-05-06 2015-09-02 山东罗欣药业集团股份有限公司 Cefetamet pivoxil hydrochloride hydrate crystals and dispersible tablet thereof
CN104940158A (en) * 2015-06-09 2015-09-30 杨玉廷 Medicine composition containing cefuroxime axetil and preparation method of medicine composition

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104876947A (en) * 2015-05-06 2015-09-02 山东罗欣药业集团股份有限公司 Cefetamet pivoxil hydrochloride hydrate crystals and dispersible tablet thereof
CN104800221A (en) * 2015-05-15 2015-07-29 苗怡文 Medicinal cefetamet pivoxil hydrochloride composition for treating sensitive bacteria infectious diseases
CN104940158A (en) * 2015-06-09 2015-09-30 杨玉廷 Medicine composition containing cefuroxime axetil and preparation method of medicine composition

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