CN106902084B - A kind of dry mix suspension grain of Cefixime - Google Patents
A kind of dry mix suspension grain of Cefixime Download PDFInfo
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- CN106902084B CN106902084B CN201710154236.4A CN201710154236A CN106902084B CN 106902084 B CN106902084 B CN 106902084B CN 201710154236 A CN201710154236 A CN 201710154236A CN 106902084 B CN106902084 B CN 106902084B
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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
- A61K9/14—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
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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
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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
- A61K9/14—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
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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
- A61K9/14—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
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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
- A61K9/14—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
- A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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Abstract
The invention discloses a kind of dry mix suspension grain of Cefixime, the component of following parts by weight is included：Cefixime 5 20%；Disintegrant 1 10%；Sweetener a 30 70%；Suspending agent 1 10%；Sweetener b 20 60%；Colouring agent 0.1 0.5%；PH adjusting agent 1 10%；Non-ionic celluloses ether 0.5 5%；Solubilizer 0.1 1.5%；Flavouring 1 3%.The dry mix suspension grain intermediate particle appearance of Cefixime of the present invention covers sweetener and colouring agent, significantly improve mouthfeel and outward appearance, and by adding pH adjusting agent, non-ionic celluloses ether and suspending particle, be advantageous to improve the dispersiveness of Cefixime in a liquid, promote the release and absorption of Cefixime in vivo.The dry mix suspension grain of Cefixime of the present invention, stability and dissolubility are improved significantly, and the increase of each principal degradation impurity is all controlled in safety, acceptable level.
Description
Technical field
The present invention relates to field of medicaments, more particularly to a kind of dry mix suspension grain of Cefixime.
Background technology
Cefixime is by the third generation of Japanese Fujisawa Pharmaceutical Co., Ltd (existing Astellas companies) research and development
Cephalosporin analog antibiotic.It has broad-spectrum antibacterial action to gram-positive bacteria and negative bacterium, particularly in gram-positive bacteria
Streptococcus, pneumococcus, gonococcus, mucositis Branhamella in Gram-negative bacteria, Escherichia coli, klebsiella
Category, Serratia, Proteus, influenza Pseudomonas etc. show the antibacterial activity more stronger than other oral cephalosporins.Absorb
After be distributed widely in whole body, drug concentration is higher；It is stable to beta-lactamase；Convenient drug administration, dosage is small, daily administration one
Secondary or twice, dosage is 50~200mg, is one of medicine that dosage is smaller in current cephalosporin analog antibiotic.
Cefixime belongs to the class medicines of BCS tetra- that indissoluble difficulty is oozed, insoluble in water, at the same the stability of Cefixime compared with
Difference, clearly, this brings bigger challenge to the exploitation of preparation for impurity increase particularly under wet heat condition, simultaneously because
By technical conditions and understanding background limited, the universal mass ratio of cefixime preparation product of early development is relatively low, stability compared with
Difference, larger gap be present with the former product that grinds in the indexs such as impurity, dissolution, domestic imitation exploitation is shown as on Clinical practice
Cefixime preparation can not grind product instead of original.
Therefore, prior art has yet to be improved and developed.
The content of the invention
In view of above-mentioned the deficiencies in the prior art, it is an object of the invention to provide a kind of dry mix suspension grain of Cefixime, purport
The cefixime preparation that solves existing exploitation is unstable, dissolubility is poor the problems such as.
Technical scheme is as follows：
A kind of dry mix suspension grain of Cefixime, wherein, by weight percentage, include following component：
The dry mix suspension grain of described Cefixime, wherein, by weight percentage, include following component：
The dry mix suspension grain of described Cefixime, wherein, the disintegrant is starch, pregelatinized starch, CMS
Sodium, hydroxypropul starch, dextrin, Ac-Di-Sol, cross-linked carboxymethyl cellulose calcium low-substituted hydroxypropyl cellulose, friendship
Join the one or more in PVP.
The dry mix suspension grain of described Cefixime, wherein, the sweetener a and the sweetener b be sucrose, fructose,
Glucose, galactolipin, xylose, lactose, maltose, mannitol, maltitol, sorbierite, xylitol, hydroxyl isomaltulose, saccharin,
One or more in acesulfame potassium, aspartame, glycyrrhizic acid, Sucralose.
The dry mix suspension grain of described Cefixime, wherein, the suspending agent is Arabic gum, tragacanth, xanthans, sea
One or more in mosanom, PVP, colloidal silica, sodium carboxymethylcellulose.
The dry mix suspension grain of described Cefixime, wherein, the colouring agent be Sunset yellow aluminum lake, Fancy red aluminum lake,
One or more in tartrazine aluminum lake, Ponceau 4R aluminum lake.
The dry mix suspension grain of described Cefixime, wherein, the pH adjusting agent be citric acid, lactic acid, tartaric acid, carbonic acid,
Sodium glutamate, malic acid, propionic acid, ethylenediamine, sodium hydroxide, sodium carbonate, potassium carbonate, sodium acid carbonate, disodium hydrogen phosphate, acetic acid
One or more in sodium, sodium citrate.
The dry mix suspension grain of described Cefixime, wherein, the non-ionic celluloses ether is methylcellulose, ethoxy
Cellulose, hydroxypropyl methyl cellulose, hydroxy butyl methyl cellulose, ethylmethylcellulose, carboxy methyl cellulose, ethyl
One kind or more in cellulose, ethylhydroxyethylcellulose, ethylmethylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose
Kind.
The dry mix suspension grain of described Cefixime, wherein, the solubilizer be lauryl sodium sulfate, rilanit special,
One or more in Tween 80, HYDROXYPROPYL BETA-CYCLODEXTRIN, PLURONICS F87.
The dry mix suspension grain of described Cefixime, wherein, the flavouring be Mint Essence, vanilla, lemon extract,
One or more in flavoring orange essence, strawberry essence, assorted savory essence.
Beneficial effect：The present invention use above-mentioned formula, the dry mix suspension grain of Cefixime being prepared, not only stability and
Dissolubility is significantly improved, and color and mouthfeel are also greatly improved, while the increase of each principal degradation impurity is all
Control is in safety, acceptable level.
Brief description of the drawings
Fig. 1 is the particle size distribution figure of Cefixime in the dry mix suspension grain of Cefixime of the present invention.
The acetate salt buffer that Fig. 2 is the dry mix suspension grain of Cefixime of the embodiment of the present invention 1 and control formulation is 4.0 in pH
Stripping curve comparison diagram in liquid.
The acetate salt buffer that Fig. 3 is the dry mix suspension grain of Cefixime of the embodiment of the present invention 2 and control formulation is 4.0 in pH
Stripping curve comparison diagram in liquid.
The acetate salt buffer that Fig. 4 is the dry mix suspension grain of Cefixime of the embodiment of the present invention 3 and control formulation is 4.0 in pH
Stripping curve comparison diagram in liquid.
The acetate salt buffer that Fig. 5 is the dry mix suspension grain of Cefixime of the embodiment of the present invention 4 and control formulation is 4.0 in pH
Stripping curve comparison diagram in liquid.
The acetate salt buffer that Fig. 6 is the dry mix suspension grain of Cefixime of the embodiment of the present invention 5 and control formulation is 4.0 in pH
Stripping curve comparison diagram in liquid.
The acetate salt buffer that Fig. 7 is the dry mix suspension grain of Cefixime of the embodiment of the present invention 6 and control formulation is 4.0 in pH
Stripping curve comparison diagram in liquid.
The acetate salt buffer that Fig. 8 is the dry mix suspension grain of Cefixime of the embodiment of the present invention 7 and control formulation is 4.0 in pH
Stripping curve comparison diagram in liquid.
The acetate salt buffer that Fig. 9 is the dry mix suspension grain of Cefixime of the embodiment of the present invention 8 and control formulation is 4.0 in pH
Stripping curve comparison diagram in liquid.
Figure 10 is that the dry mix suspension grain of Cefixime of the embodiment of the present invention 9 and control formulation are delayed in the pH acetate for being 4.0
Stripping curve comparison diagram in fliud flushing.
Embodiment
The invention provides a kind of dry mix suspension grain of Cefixime, and illustrate its specific preparation method.To make the present invention
Purpose, technical scheme and effect it is clearer, clear and definite, the present invention is described in more detail below.It should be appreciated that this place
The specific embodiment of description only to explain the present invention, is not intended to limit the present invention.
The present invention provides a kind of dry mix suspension grain of Cefixime, wherein, by weight percentage, include following component：
The present invention uses above-mentioned formula, and the dry mix suspension grain of Cefixime being prepared, not only stability and dissolubility obtain
To significantly improving, color and mouthfeel are also greatly improved, while the increase of each principal degradation impurity is all controlled and pacified
Entirely, acceptable level
Preferably, by weight percentage, the dry mix suspension grain of Cefixime of the present invention includes following component：
According to above-mentioned formula, present invention also offers a kind of preparation method of the dry mix suspension grain of Cefixime, wherein, including
Following steps：
Step A, after taking Cefixime, disintegrant, sweetener a and suspending agent after sieving to be respectively sufficiently mixed, profit is added
Softwood is made in humectant, by drying process after sieving, obtains the dry-mixed outstanding intermediate particle of Cefixime.
The particle size distribution figure of Cefixime of the present invention is as shown in figure 1, wherein, 5 μm of Dv (10) ＜；30um ＜ Dv (50)
＜ 70um；Dv (90) ＞ 100um.Wherein Dv (Volume Density) is bulk density.
Preferably, the disintegrant can be starch, pregelatinized starch, sodium carboxymethyl starch, hydroxypropul starch, dextrin,
Ac-Di-Sol, cross-linked carboxymethyl cellulose calcium low-substituted hydroxypropyl cellulose, cross-linking polyethylene pyrrolidone
One or more in.
Preferably, the sweetener a can be sucrose, fructose, glucose, galactolipin, xylose, lactose, maltose, sweet dew
In alcohol, maltitol, sorbierite, xylitol, hydroxyl isomaltulose, saccharin, acesulfame potassium, aspartame, glycyrrhizic acid, Sucralose etc.
One or more.
Preferably, the suspending agent can be Arabic gum, tragacanth, xanthans, sodium alginate, PVP, colloidal state
One or more in silica, sodium carboxymethylcellulose etc..
Above-mentioned steps A is specifically included：Under the conditions of 20-24 DEG C/45-65%RH (relative humidity), Cefixime, disintegration are taken
After agent, sweetener a, suspending agent cross 80 mesh sieves respectively, it is added in multidirectional mixer and mixes 15-30min, after being sufficiently mixed, then
The ethanol solution for adding 0-85% (volume ratio) is used as wetting agent, and 30 mesh sieves of mistake after softwood are made, then by fluid bed≤
Fluidized drying 0.5-1.5h, preferably 1h under the conditions of 50 DEG C, obtain the dry-mixed outstanding intermediate particle of Cefixime.
Step A of the present invention is wet-granulation process after conventional material mixing, using wet granulation technology so that cephalo gram
Oxime is fully fused with the auxiliary material through fully crushing, and reaches dispersed effect.
Step B, take sweetener b, colouring agent and non-ionic celluloses ether in solvent to after fully dissolving, add pH and adjust
Save agent and adjust pH value to 1-5, be then sprayed on the dry-mixed outstanding intermediate particle surface of Cefixime, through drying process, be eventually adding increasing
Solvent and flavouring, it is well mixed, obtains the dry mix suspension grain of Cefixime.
Preferably, the sweetener b can be sucrose, fructose, glucose, galactolipin, xylose, lactose, maltose, sweet dew
In alcohol, maltitol, sorbierite, xylitol, hydroxyl isomaltulose, saccharin, acesulfame potassium, aspartame, glycyrrhizic acid, Sucralose etc.
One or more.
Preferably, the colouring agent can be Sunset yellow aluminum lake, Fancy red aluminum lake, tartrazine aluminum lake, famille rose
One or more in aluminum lake etc..
Preferably, the non-ionic celluloses ether can be methylcellulose, hydroxyethyl cellulose, hydroxypropyl methyl fibre
It is fine to tie up element, hydroxy butyl methyl cellulose, ethylmethylcellulose, carboxy methyl cellulose, ethyl cellulose, ethyl-hydroxyethyl
Tie up the one or more in element, ethylmethylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose etc..
After non-ionic celluloses ether of the present invention is dissolved in water, the solution with certain viscosity, its solution viscosity are formed
It is closely related with the pH value of solution.Highly viscous liquid is unfavorable for the dispersed of colouring agent, easily causes shower nozzle clogging,
Using the pH of the pH adjusting agent regulation aqueous solution, can solve this problem, while also there is one to be fixed to preparation dissolution and stability
Ring.Sweetener b, colouring agent and non-ionic celluloses ether of the present invention are to the auxiliary material solution ph after abundant dissolving in solvent
3-9, and the pH value for reducing auxiliary material solution advantageously reduces solution viscosity, therefore, it is molten that the present invention adds pH adjusting agent regulation auxiliary material
For the pH value of liquid to 1-5, preferable pH value is 3-4.Preferably, the pH adjusting agent can be citric acid, lactic acid, tartaric acid, carbon
Acid, phosphoric acid, sodium glutamate, malic acid, propionic acid, ethylenediamine, sodium hydroxide, sodium carbonate, potassium carbonate, sodium acid carbonate, phosphoric acid hydrogen two
One or more in sodium, sodium acetate, sodium citrate etc..The present invention is in most preferably pH by pH adjusting agent auxiliary material solution
It is worth scope so that colouring agent is dispersed, increases the stability of Cefixime.
Preferably, the solubilizer can be lauryl sodium sulfate, rilanit special, Tween 80, hydroxypropyl times his ring
One or more in dextrin, PLURONICS F87 etc..
Preferably, the flavouring can be Mint Essence, vanilla, lemon extract, flavoring orange essence, strawberry essence,
One or more in assorted savory essence etc..
Above-mentioned steps B is specifically included：Sweetener b, colouring agent and non-ionic celluloses ether is taken to add to 0-50% (volumes
Than) in ethanol solution, preferably by condition of the temperature control of ethanol solution at≤40 DEG C, in favor of the abundant dissolving of auxiliary material, fill
Divide and auxiliary material solution is obtained after dissolving, after addition pH adjusting agent regulation pH value to 1-5, auxiliary material solution is slowly sprayed on Cefixime and done
Suspension intermediate particle surface, 0.5-1.5h is dried under the conditions of 30-50 DEG C, 1h is preferably dried under the conditions of 40 DEG C, added and increase
Solvent and flavouring mix 10-30min (such as 20min) into multidirectional mixer, obtain the dry mix suspension grain of Cefixime.
Step B of the present invention for spraying inclusion process, pass through spray inclusion so that intermediate particle appearance cover sweetener and
Toner, mouthfeel and outward appearance are significantly improved, and by adding pH adjusting agent, non-ionic celluloses ether and suspending agent, favorably
In improving Cefixime dispersiveness in a liquid and stripping property, promote the release and absorption of Cefixime in vivo.
The dry mix suspension grain of Cefixime that the above method of the present invention is prepared, not only improve the dissolubility of Cefixime
And stability, the difficulty that Cefixime is easily degraded is overcome, the smell and mouthfeel of product are further improved, so as to improve patient's
Compliance.
The dry mix suspension grain of Cefixime of the present invention is applied to field of medicaments, available for treatment ear nose larynx infection, as tympanitis,
Nasosinusitis；Urinary system infection contamination, such as pyelonephritis, cystitis, urethritis；ALRI, such as acute bronchitis, lung
The scorching, superinfection of chronic respiratory device lesion；It can also be used for scarlatinous treatment.
The dry mix suspension grain of Cefixime of the present invention exists in the form of granules, with solution or suspension during oral administration
Form is administered or taken together with drinking water, and single dose includes Cefixime 50mg.Into human oral dosage form, general 50~100mg,
2 times a day；The general oral dose of pediatric pharmaceuticalses is 1.5~3mg/kg, by batheroom scale, 2 times a day.
Below by embodiment, the present invention is described in detail.
Embodiment 1
Preparation process is as follows：
First step：Under the conditions of 23 DEG C/55%RH, Cefixime, disintegrant, sweetener a, suspending agent is taken to cross 80 respectively
After mesh sieve, it is placed in multidirectional mixer and mixes 15min, adds 50% ethanol as wetting agent, cross 30 mesh sieves after softwood is made, so
Afterwards by fluid bed drying process under the conditions of 50 DEG C, the dry-mixed outstanding intermediate particle of Cefixime is obtained；Second step is specifically to take
Sweetener b, colouring agent and hydroxypropyl methyl cellulose are added in 50% ethanol solution, are fully obtained auxiliary material solution after dissolving, are added
Enter pH adjusting agent and adjust pH value to after 3.0, the dry-mixed outstanding intermediate particle surface of Cefixime is slowly sprayed on, at 40 DEG C of drying
Reason, is eventually adding solubilizer and flavouring and mixes 15min in multidirectional mixer, obtain the dry mix suspension grain of Cefixime.Prepare
During, each component addition see the table below 1.
Each component content in the dry mix suspension grain of table 1, Cefixime
| Composition | Ratio (weight is than %) |
| Cefixime | 5% |
| Disintegrant-dextrin | 3% |
| Solubilizer-lauryl sodium sulfate | 0.5% |
| Sweetener 1- lactose | 49.4% |
| Sweetener 2- lactose | 30% |
| Suspending agent-tragacanth | 3% |
| Colouring agent-Sunset yellow aluminum lake | 0.1% |
| PH adjusting agent-tartaric acid | 4% |
| Hydroxypropyl methyl cellulose | 4% |
| Flavouring-assorted savory essence | 1% |
The present invention carries out stripping curve and relevant material to the dry mix suspension grain of Cefixime resulting in above example
Check, as a result see Fig. 2, table 2 below.Calculated according to F2 similarity estimates, the stripping curve similarity of embodiment 1 and control formulation is
68.8。
The present invention is due to that the medium has stronger resolution ratio using pH4.0 acetate buffers as dissolution medium, and
Detection time is shorter.
Cefixime is mainly influenced by temperature larger, and relevant material changes significantly under the conditions of high temperature (60 DEG C),
Without significant change in high humidity (92.5%RH) and illumination (1.2 × 106Luxhr of total illumination).
Table 2, the high temperature of embodiment 1 (60 DEG C) Related substances separation
Embodiment 2
Preparation process is as follows：
First step：Under the conditions of 22 DEG C/60%RH, Cefixime, disintegrant, sweetener a, suspending agent is taken to cross 80 respectively
After mesh sieve, it is placed in multidirectional mixer and mixes 25min, adds 50% ethanol as wetting agent, cross 30 mesh sieves after softwood is made, so
Afterwards by fluid bed drying process under the conditions of 45 DEG C, the dry-mixed outstanding intermediate particle of Cefixime is obtained；Second step is specifically to take
Sweetener b, colouring agent and hydroxypropyl methyl cellulose are added in 30% ethanol solution, are fully obtained auxiliary material solution after dissolving, are added
PH adjusting agent adjusts pH value to after 3.5, is slowly sprayed on the dry-mixed outstanding intermediate particle surface of Cefixime, through 40 DEG C of drying and processings,
It is eventually adding solubilizer and flavouring and mixes 20min in multidirectional mixer, obtains the dry mix suspension grain of Cefixime.Preparation process
In, each component addition see the table below 3.
Each component content in the dry mix suspension grain of table 3, Cefixime
The present invention carries out stripping curve and relevant material to the dry mix suspension grain of Cefixime resulting in above example
Check, as a result see Fig. 3, table 4 below.Calculated according to F2 similarity estimates, the stripping curve similarity of embodiment 2 and control formulation is
68.8。
Table 4, the high temperature of embodiment 2 (60 DEG C) Related substances separation
Embodiment 3
Preparation process is as follows：
First step：Under the conditions of 21 DEG C/65%RH, Cefixime, disintegrant, sweetener a, suspending agent is taken to cross 80 respectively
After mesh sieve, it is placed in multidirectional mixer and mixes 30min, adds 75% ethanol as wetting agent, cross 30 mesh sieves after softwood is made, so
Afterwards by fluid bed drying process under the conditions of 40 DEG C, the dry-mixed outstanding intermediate particle of Cefixime is obtained；Second step is specifically to take
Sweetener b, colouring agent and hydroxypropyl methyl cellulose are added in 30% ethanol solution, are fully obtained auxiliary material solution after dissolving, are added
PH adjusting agent adjusts pH value to after 3.8, is slowly sprayed on the dry-mixed outstanding intermediate particle surface of Cefixime, through 40 DEG C of drying and processings,
It is eventually adding solubilizer and flavouring and mixes 30min in multidirectional mixer, obtains the dry mix suspension grain of Cefixime.Preparation process
In, each component addition see the table below 5.
Each component content in the dry mix suspension grain of table 5, Cefixime
| Composition | Ratio (weight is than %) |
| Cefixime | 15% |
| Disintegrant-pre-paying starch | 7% |
| Solubilizer-HYDROXYPROPYL BETA-CYCLODEXTRIN | 1.40% |
| Sweetener 1- sucrose | 31.40% |
| Sweetener 2- lactose | 28% |
| Suspending agent-Arabic gum | 5% |
| Colouring agent-tartrazine aluminum lake | 0.11% |
| PH adjusting agent-malic acid | 8% |
| Ethyl cellulose | 3% |
| Flavouring-flavoring orange essence | 1.10% |
The present invention carries out stripping curve and relevant material to the dry mix suspension grain of Cefixime resulting in above example
Check, as a result see Fig. 4, table 6 below.Calculated according to F2 similarity estimates, the stripping curve similarity of embodiment 3 and control formulation is
60.7。
Table 6, the high temperature of embodiment 3 (60 DEG C) Related substances separation
Embodiment 4
Preparation process is as follows：
First step：Under the conditions of 23 DEG C/55%RH, Cefixime, disintegrant, sweetener a, suspending agent is taken to cross 80 respectively
After mesh sieve, it is placed in multidirectional mixer and mixes 15min, adds purified water as wetting agent, cross 30 mesh sieves after softwood is made, then
By fluid bed drying process under the conditions of 50 DEG C, the dry-mixed outstanding intermediate particle of Cefixime is obtained；Second step is specifically to take sweet tea
Taste agent b, colouring agent and hydroxypropyl methyl cellulose are added in 50% ethanol solution, are fully obtained auxiliary material solution after dissolving, are added pH
Conditioning agent adjusts pH value to after 3.0, is slowly sprayed on the dry-mixed outstanding intermediate particle surface of Cefixime, through 40 DEG C of drying and processings, most
Add solubilizer afterwards and flavouring mixes 15min in multidirectional mixer, obtain the dry mix suspension grain of Cefixime.Preparation process
In, each component addition is shown in Table 7.
Each component content in the dry mix suspension grain of table 7, Cefixime
The present invention carries out stripping curve and relevant material to the dry mix suspension grain of Cefixime resulting in above example
Check, as a result see Fig. 5, table 8 below.Calculated according to F2 similarity estimates, the stripping curve similarity of embodiment 4 and control formulation is
75.8。
Table 8, the high temperature of embodiment 4 (60 DEG C) Related substances separation
Embodiment 5
Preparation process is as follows：
First step：Under the conditions of 22 DEG C/60%RH, Cefixime, disintegrant, sweetener a, suspending agent is taken to cross 80 respectively
After mesh sieve, it is placed in multidirectional mixer and mixes 25min, adds 50% ethanol as wetting agent, cross 30 mesh sieves after softwood is made, so
Afterwards by fluid bed drying process under the conditions of 45 DEG C, the dry-mixed outstanding intermediate particle of Cefixime is obtained；Second step is specifically to take
Sweetener b, colouring agent and hydroxypropyl methyl cellulose are added in 30% ethanol solution, are fully obtained auxiliary material solution after dissolving, are added
PH adjusting agent adjusts pH value to after 3.5, is slowly sprayed on the dry-mixed outstanding intermediate particle surface of Cefixime, through 40 DEG C of drying and processings,
It is eventually adding solubilizer and flavouring and mixes 20min in multidirectional mixer, obtains the dry mix suspension grain of Cefixime.Preparation process
In, each component addition see the table below 9.
Each component content in the dry mix suspension grain of table 9, Cefixime
| Composition | Ratio (weight is than %) |
| Cefixime | 10% |
| Disintegrant-Ac-Di-Sol | 4% |
| Solubilizer-Tween 80 | 1.1% |
| Sweetener 1- mannitol | 40.5% |
| Sweetener 2- mannitol | 29% |
| Suspending agent-xanthans | 3% |
| Colouring agent-Fancy red aluminum lake | 0.1% |
| PH adjusting agent-citric acid | 6% |
| Hydroxypropyl cellulose | 5% |
| Flavouring-strawberry essence | 1.3% |
The present invention carries out stripping curve and relevant material to the dry mix suspension grain of Cefixime resulting in above example
Check, as a result see Fig. 6, table 10 below.Calculated according to F2 similarity estimates, the stripping curve similarity of embodiment 5 and control formulation
For 62.4.
Table 10, the high temperature of embodiment 5 (60 DEG C) Related substances separation
Embodiment 6
Preparation process is as follows：
First step：Under the conditions of 21 DEG C/65%RH, Cefixime, disintegrant, sweetener a, suspending agent is taken to cross 80 respectively
After mesh sieve, it is placed in multidirectional mixer and mixes 30min, adds 75% ethanol as wetting agent, cross 30 mesh sieves after softwood is made, so
Afterwards by fluid bed drying process under the conditions of 40 DEG C, the dry-mixed outstanding intermediate particle of Cefixime is obtained；Second step is specifically to take
Sweetener b, colouring agent and hydroxypropyl methyl cellulose are added in 30% ethanol solution, are fully obtained auxiliary material solution after dissolving, are added
PH adjusting agent adjusts pH value to after 3.8, is slowly sprayed on the dry-mixed outstanding intermediate particle surface of Cefixime, through 40 DEG C of drying and processings,
It is eventually adding solubilizer and flavouring and mixes 30min in multidirectional mixer, obtains the dry mix suspension grain of Cefixime.Preparation process
In, each component addition see the table below 11.
Each component content in the dry mix suspension grain of table 11, Cefixime
| Composition | Ratio (weight is than %) |
| Cefixime | 15% |
| Disintegrant-starch | 7% |
| Solubilizer-HYDROXYPROPYL BETA-CYCLODEXTRIN | 1.40% |
| Sweetener 1- sucrose | 31.40% |
| Sweetener 2- mannitol | 28% |
| Suspending agent-Arabic gum | 5% |
| Colouring agent-tartrazine aluminum lake | 0.11% |
| PH adjusting agent-malic acid | 8% |
| Ethyl cellulose | 3% |
| Flavouring-flavoring orange essence | 1.10% |
The present invention carries out stripping curve and relevant material to the dry mix suspension grain of Cefixime resulting in above example
Check, as a result see Fig. 7, table 12 below.Calculated according to F2 similarity estimates, the stripping curve similarity of embodiment 6 and control formulation
For 62.4.
Table 12, the high temperature of embodiment 6 (60 DEG C) Related substances separation
Embodiment 7
Preparation process is as follows：
First step：Under the conditions of 23 DEG C/55%RH, Cefixime, disintegrant, sweetener a, suspending agent is taken to cross 80 respectively
After mesh sieve, it is placed in multidirectional mixer and mixes 15min, adds purified water as wetting agent, cross 30 mesh sieves after softwood is made, then
By fluid bed drying process under the conditions of 50 DEG C, the dry-mixed outstanding intermediate particle of Cefixime is obtained；Second step is specifically to take sweet tea
Taste agent b, colouring agent and hydroxypropyl methyl cellulose are added in 50% ethanol solution, are fully obtained auxiliary material solution after dissolving, are added pH
Conditioning agent adjusts pH value to after 3.0, is slowly sprayed on the dry-mixed outstanding intermediate particle surface of Cefixime, through 40 DEG C of drying and processings, most
Add solubilizer afterwards and flavouring mixes 15min in multidirectional mixer, obtain the dry mix suspension grain of Cefixime.Preparation process
In, each component addition see the table below 13.
Each component content in the dry mix suspension grain of table 13, Cefixime
The present invention carries out stripping curve and relevant material to the dry mix suspension grain of Cefixime resulting in above example
Check, as a result see Fig. 8, table 14 below.Calculated according to F2 similarity estimates, the stripping curve similarity of embodiment 7 and control formulation
For 61.2.
Table 14, the high temperature of embodiment 7 (60 DEG C) Related substances separation
Embodiment 8
Preparation process is as follows：
First step：Under the conditions of 22 DEG C/60%RH, Cefixime, disintegrant, sweetener a, suspending agent is taken to cross 80 respectively
After mesh sieve, it is placed in multidirectional mixer and mixes 25min, adds 50% ethanol as wetting agent, cross 30 mesh sieves after softwood is made, so
Afterwards by fluid bed drying process under the conditions of 45 DEG C, the dry-mixed outstanding intermediate particle of Cefixime is obtained；Second step is specifically to take
Sweetener b, colouring agent and hydroxypropyl methyl cellulose are added in 30% ethanol solution, are fully obtained auxiliary material solution after dissolving, are added
PH adjusting agent adjusts pH value to after 3.5, is slowly sprayed on the dry-mixed outstanding intermediate particle surface of Cefixime, through 40 DEG C of drying and processings,
It is eventually adding solubilizer and flavouring and mixes 20min in multidirectional mixer, obtains the dry mix suspension grain of Cefixime.Preparation process
In, each component addition see the table below 15.
Each component content in the dry mix suspension grain of table 15, Cefixime
| Composition | Ratio (weight is than %) |
| Cefixime | 10% |
| Disintegrant-cross-linked carboxymethyl cellulose calcium | 4% |
| Solubilizer-Tween 80 | 1.1% |
| Sweetener 1- mannitol | 40.5% |
| Sweetener 2- sucrose | 29% |
| Suspending agent-xanthans | 3% |
| Colouring agent-Fancy red aluminum lake | 0.1% |
| PH adjusting agent-citric acid | 6% |
| Hydroxypropyl cellulose | 5% |
| Flavouring-strawberry essence | 1.3% |
The present invention carries out stripping curve and relevant material to the dry mix suspension grain of Cefixime resulting in above example
Check, as a result see Fig. 9, table 16 below.Calculated according to F2 similarity estimates, the stripping curve similarity of embodiment 8 and control formulation
For 58.2.
Table 16, the high temperature of embodiment 8 (60 DEG C) Related substances separation
Embodiment 9
Preparation process is as follows：
First step：Under the conditions of 21 DEG C/65%RH, Cefixime, disintegrant, sweetener a, suspending agent is taken to cross 80 respectively
After mesh sieve, it is placed in multidirectional mixer and mixes 30min, adds 75% ethanol as wetting agent, cross 30 mesh sieves after softwood is made, so
Afterwards by fluid bed drying process under the conditions of 40 DEG C, the dry-mixed outstanding intermediate particle of Cefixime is obtained；Second step is specifically to take
Sweetener b, colouring agent and hydroxypropyl methyl cellulose are added in 30% ethanol solution, are fully obtained auxiliary material solution after dissolving, are added
PH adjusting agent adjusts pH value to after 3.8, is slowly sprayed on the dry-mixed outstanding intermediate particle surface of Cefixime, through 40 DEG C of drying and processings,
It is eventually adding solubilizer and flavouring and mixes 30min in multidirectional mixer, obtains the dry mix suspension grain of Cefixime.Preparation process
In, each component addition see the table below 17.
Each component content in the dry mix suspension grain of table 17, Cefixime
The present invention carries out stripping curve and relevant material to the dry mix suspension grain of Cefixime resulting in above example
Check, as a result see Figure 10, table 18 below.Calculated according to F2 similarity estimates, the stripping curve similarity of embodiment 9 and control formulation
For 67.7.
Table 18, the high temperature of embodiment 9 (60 DEG C) Related substances separation
In summary, the invention provides a kind of dry mix suspension grain of Cefixime, the dry mix suspension grain of Cefixime of the present invention
Intermediate particle appearance covers sweetener and colouring agent, significantly improves mouthfeel and outward appearance, and by add pH adjusting agent, it is non-from
Subtype cellulose ether and suspending particle, be advantageous to improve the dispersiveness of Cefixime in a liquid, promote Cefixime in vivo
Release and absorption.The dry mix suspension grain of Cefixime provided by the invention, stability is improved significantly, and each principal degradation is miscellaneous
The increase of matter is all controlled in safety, acceptable level；Compared with former triturate, stripping curve similarity reaches more than 50 (F2 phases
Like factorization method).
It should be appreciated that the application of the present invention is not limited to above-mentioned citing, for those of ordinary skills, can
To be improved or converted according to the above description, all these modifications and variations should all belong to the guarantor of appended claims of the present invention
Protect scope.
Claims (3)
1. a kind of dry mix suspension grain of Cefixime, it is characterised in that by weight percentage, include following component：
Cefixime 5-20%；
Disintegrant 1-10%；
Sweetener a 30-70%；
Suspending agent 1-10%；
Sweetener b 20-60%；
Colouring agent 0.1-0.5%；
PH adjusting agent 1-10%；
Non-ionic celluloses ether 0.5-5%；
Solubilizer 0.1-1.5%；
Flavouring 1-3%；
The preparation method of the dry mix suspension grain of Cefixime comprises the following steps：
Step A：Under the conditions of 20-24 DEG C/45-65% RH, Cefixime, disintegrant, sweetener a, suspending agent is taken to cross 80 respectively
After mesh sieve, it is added in multidirectional mixer and mixes 15-30min, after being sufficiently mixed, it is molten adds the ethanol that volume ratio is 0-85%
Liquid crosses 30 mesh sieves as wetting agent after softwood is made, then by fluid bed under the conditions of≤50 DEG C fluidized drying 0.5-1.5h,
Obtain the dry-mixed outstanding intermediate particle of Cefixime；
Step B：Sweetener b, colouring agent and non-ionic celluloses ether is taken to after fully dissolving, to add pH adjusting agent in solvent
PH value is adjusted to 1-5, the dry-mixed outstanding intermediate particle surface of Cefixime is then sprayed on, through drying process, is eventually adding solubilizer
And flavouring, it is well mixed, obtains the dry mix suspension grain of Cefixime；
The disintegrant is starch, pregelatinized starch, hydroxypropul starch, dextrin, Ac-Di-Sol, cross-linked carboxymethyl
One or more in cellulose calcium, low-substituted hydroxypropyl cellulose, cross-linking polyethylene pyrrolidone；
The sweetener a and sweetener b is the one or more in sucrose, lactose, mannitol；
The suspending agent is the one or more in Arabic gum, tragacanth, xanthans；
The non-ionic celluloses ether be hydroxypropyl methyl cellulose, ethyl cellulose, one kind in hydroxypropyl cellulose or
It is a variety of；
The pH adjusting agent is the one or more in citric acid, tartaric acid, malic acid；
The solubilizer is the one or more in lauryl sodium sulfate, Tween 80, HYDROXYPROPYL BETA-CYCLODEXTRIN；
The flavouring is one in Mint Essence, vanilla, lemon extract, flavoring orange essence, strawberry essence, assorted savory essence
Kind is a variety of.
2. the dry mix suspension grain of Cefixime according to claim 1, it is characterised in that by weight percentage, comprising such as
Lower component：
Cefixime 5-15%；
Disintegrant 3-7%；
Sweetener a 30-50%；
Suspending agent 3-6%；
Sweetener b 20-40%；
Colouring agent 0.1-0.2%；
PH adjusting agent 4-8%；
Non-ionic celluloses ether 3-5%；
Solubilizer 1.0-1.5%；
Flavouring 1-2%.
3. the dry mix suspension grain of Cefixime according to claim 1 or 2, it is characterised in that the colouring agent is sunset yellow
One or more in aluminum lake, Fancy red aluminum lake, tartrazine aluminum lake, Ponceau 4R aluminum lake.
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| CN112999166B (en) * | 2019-12-19 | 2024-05-03 | 康普药业股份有限公司 | Cefixime preparation |
| CN112402391A (en) * | 2020-12-16 | 2021-02-26 | 湖北凌晟药业有限公司 | Cefcapene pivoxil granules and preparation method thereof |
| CN116059331B (en) * | 2022-12-14 | 2023-09-19 | 佛山市正典生物技术有限公司 | Suspending agent granule and preparation method and application thereof |
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| CN103405387B (en) * | 2013-08-13 | 2015-11-04 | 江苏正大清江制药有限公司 | A kind of new Cefixime suspension and preparation method thereof |
| CN103622916B (en) * | 2013-12-19 | 2015-04-08 | 石家庄市华新药业有限责任公司 | Cefixime dry suspension and preparation method thereof |
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