CN110075079A - A kind of appropriate logical sequence pivoxil plain piece of spore, the appropriate logical sequence pivoxil piece of spore and preparation method - Google Patents
A kind of appropriate logical sequence pivoxil plain piece of spore, the appropriate logical sequence pivoxil piece of spore and preparation method Download PDFInfo
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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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
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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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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Abstract
The invention discloses a kind of appropriate logical sequence pivoxil plain piece of spore, the appropriate logical sequence pivoxil piece of spore and preparation methods.The preparation method of the appropriate logical sequence pivoxil plain piece of spore, comprising steps of unformed Cefditoren pivoxil Cephalosporins is dried, the water content of the unformed Cefditoren pivoxil Cephalosporins after control is dry is less than 1%；Filler, disintegrating agent, lubricant are mixed with the unformed Cefditoren pivoxil Cephalosporins after drying, obtain mixed material；The mixed material is subjected to tabletting, obtains Cefditoren pivoxil Cephalosporins plain piece.The processing step of preparation method of the present invention is simple, the content of moisture in easily controllable preparation, thus in easily controllable production process the appropriate logical sequence pivoxil of spore crystal form；Energy consumption is lower simultaneously, and the limiting factor of batch is less, is easy to large-scale industrial production.
Description
Technical field
The present invention relates to pharmaceuticals field more particularly to a kind of appropriate logical sequence pivoxil plain pieces of spore, the appropriate logical sequence pivoxil piece of spore and preparation side
Method.
Background technique
Cefditoren pivoxil Cephalosporins was the oral cephalo-type broad-spectrum antibiotic of Japanese MingZhi fruit Co., Ltd's exploitation, in 1994
April 1 listed in Japan for the first time, and exploitation dosage form is tablet, granule (Japan claims granula subtilis), and tablet and granule take at present
Obtained the import of drugs registration certification in China.
Cefditoren pivoxil Cephalosporins (Cefditoren Pivoxil) chemical name are as follows: (-)-(6R, 7R) -2,2- dimethyl propionyl
Oxygen methyl 7- [(Z) -2- (2- amino -4- thiazolyl) -2- methoxyl group imido acetylamino] -3- [(Z) -2- (4- methyl -5- thiophene
Oxazolyl) vinyl] -8- oxo -5- thia -1- azabicyclic [4.2.0] oct-2-ene -2- carboxylate, molecular formula is
C25H28N6O7S3, molecular weight 620.73
Chemical structural formula is as follows:
Cefditoren pivoxil Cephalosporins is that it is appropriate to be broken down into cephalo in intestinal tube wall after taking orally Cefditoren pivoxil Cephalosporins for antibacterial type antibiotic
Logical sequence and enter the circulatory system, the mechanism of action of cefoperon is to inhibit bacteria cell wall synthesis, in conjunction with various bacterium penicillin
The compatibility of albumen (PBP) is high, to play bactericidal properties effect.
The In vitro Bactericidal Experiments of cefoperon show that it has extensive antimicrobial spectrum to gram positive bacteria and negative bacterium, especially
To staphylococcus, the gram positive bacterias such as streptococcus including streptococcus pneumonia, escherichia coli, catarrh Blanc Chinese ball
The gram-negative bacterias such as bacterium, Klebsiella, Proteus, haemophilus influenzae and Peptostreptococcus, acne propionic acid bar
The anaerobic bacterias such as bacterium, Bacteroides show very strong antimicrbial power.Cefoperon stablizes various bacteriogenic beta-lactamases, to production
Beta-lactamase bacterial strain also shows very strong antimicrbial power.
Cefditoren pivoxil Cephalosporins is suitable for epifolliculitis, furuncle, furuncle disease, carbuncle, contagious ecthyma sore, pellet caused by sensitive bacterial
Poison, cellulitis, lymphatic vessel (knot) inflammation, pyogenic paronychia, the pyogenic infection of the pad of a finger, subcutaneous abscess, spiradenitis, infectious sebaceous cyst, chronic purulence
Skin disease；Mazoitis, perianal abscess, the shallow property secondary infection of table for injuring surgical wound surface outside etc.；Sphagitis (throat abscess),
Acute bronchitis, tonsillitis (periamygdalitis, circumtonsillar abscess), chronic bronchitis, bronchiectasis
(when infection), the secondary infection of chronic respiratory illness, pneumonia, pulmonary suppuration disease；Pyelonephritis, cystitis；Cholecystitis, cholangitis；
Adnexitis, intra-uterine infection, bartholinitis；Tympanitis, paranasal sinusitis；Blepharitis, sty, palpebral abscess, tarsus
Adenositis, dacryocystitis；Periodontitis, pericoronitis, ganathitis.
Cefditoren pivoxil Cephalosporins has crystal type and unformed two states, and crystal form Cefditoren pivoxil Cephalosporins stability is preferable, still
Its dissolubility is poor, is unfavorable for clinical absorption；The dissolubility of unformed Cefditoren pivoxil Cephalosporins is preferable, and oral absorption is substantially better than knot
The Cefditoren pivoxil Cephalosporins of crystal form, but its stability is poor, is easily converted to the Cefditoren pivoxil Cephalosporins of crystal type.Existing patent or text
It offers and discloses the preparation technique for turning crystal technique and unformed Cefditoren pivoxil Cephalosporins of Cefditoren pivoxil Cephalosporins, but there are process conditions to answer
Using type, more, solvent removes the problems such as difficult, product general stability is bad to miscellaneous, auxiliary material.
Therefore, the existing technology needs to be improved and developed.
Summary of the invention
In view of above-mentioned deficiencies of the prior art, the purpose of the present invention is to provide a kind of appropriate logical sequence pivoxil plain pieces of spore, the appropriate logical sequence of spore
Pivoxil piece and preparation method, it is intended to process conditions are complicated in the prior art, auxiliary material is more using type, solvent removal is difficult for solution,
Cefditoren pivoxil Cephalosporins tablet dissolution is low, the problem of product stability difference.
A kind of preparation method of the appropriate logical sequence pivoxil plain piece of spore, wherein comprising steps of
Unformed Cefditoren pivoxil Cephalosporins is dried, the water content of the unformed Cefditoren pivoxil Cephalosporins after control is dry is small
In 1%；
Filler, disintegrating agent, lubricant are mixed with the unformed Cefditoren pivoxil Cephalosporins after drying, obtain mixture
Material；
The mixed material is subjected to tabletting, obtains Cefditoren pivoxil Cephalosporins plain piece.
The preparation method of the appropriate logical sequence pivoxil plain piece of the spore, wherein described by filler, disintegrating agent, lubricant and drying
Unformed Cefditoren pivoxil Cephalosporins afterwards carries out mixing and specifically includes:
Filler is mixed with disintegrating agent, obtains mixed accessories；
The mixed accessories are mixed with the unformed Cefditoren pivoxil Cephalosporins after drying, obtain premix material；
The premix material is mixed with lubricant, obtains mixed material.
The preparation method of the appropriate logical sequence pivoxil plain piece of the spore, wherein the filler microcrystalline cellulose, pregelatinized starch,
One of dicalcium phosphate dihydrate, mannitol, calcium sulphate dihydrate.
The preparation method of the appropriate logical sequence pivoxil plain piece of the spore, wherein the disintegrating agent pregelatinized starch, cross-linked carboxymethyl are fine
Tie up one of plain sodium, carboxyrnethyl starch sodium, cross-linked carboxymethyl cellulose calcium or a variety of.
The preparation method of the appropriate logical sequence pivoxil plain piece of the spore, wherein the lubricant is stearic acid, magnesium stearate, tristearin
One of sour calcium, sodium stearyl fumarate, rilanit special are a variety of.
The preparation method of the appropriate logical sequence pivoxil plain piece of the spore, wherein described that unformed Cefditoren pivoxil Cephalosporins is dried
Drying temperature be 50 DEG C or less.
The preparation method of the appropriate logical sequence pivoxil plain piece of the spore, wherein unformed Cefditoren pivoxil Cephalosporins is done described
It further include that pulverization process is carried out to the unformed Cefditoren pivoxil Cephalosporins after drying after dry.
A kind of appropriate logical sequence pivoxil plain piece of spore, wherein be prepared using the preparation method of the appropriate logical sequence pivoxil plain piece of spore as described above.
A kind of preparation method of the appropriate logical sequence pivoxil piece of spore, wherein the appropriate logical sequence pivoxil plain piece of spore as described above is coated, is prepared
Obtain the appropriate logical sequence pivoxil piece of spore.
A kind of appropriate logical sequence pivoxil piece of spore, wherein be prepared using the preparation method of the appropriate logical sequence pivoxil piece of spore as described above.
The utility model has the advantages that the processing step of preparation process of the present invention is simple, the content of moisture in easily controllable preparation, from
And in easily controllable production process the appropriate logical sequence pivoxil of spore crystal form；The preparation process energy consumption is lower simultaneously, the limiting factor of batch
It is less, it is easy to large-scale industrial production.While simplifying preparation process, Cefditoren pivoxil Cephalosporins piece prepared by the present invention has
Good product dissolution, other quality index also comply with standard requirements, and it is consistent that quality with original grinds product.
Specific embodiment
The present invention provides a kind of appropriate logical sequence pivoxil plain piece of spore, the appropriate logical sequence pivoxil piece of spore and preparation method, for make the purpose of the present invention,
Technical solution and effect are clearer, clear, and the present invention is described in more detail below.It should be appreciated that described herein
Specific embodiment is only used to explain the present invention, is not intended to limit the present invention.
A kind of Cefditoren pivoxil Cephalosporins composition, wherein in parts by weight, comprising:
Wherein, the water content of the unformed Cefditoren pivoxil Cephalosporins is less than 1%.
Unformed Cefditoren pivoxil Cephalosporins in Cefditoren pivoxil Cephalosporins composition of the present invention refers to the medicinal of Cefditoren pivoxil Cephalosporins
Crystal form is unformed.Compared with crystal type Cefditoren pivoxil Cephalosporins, unformed Cefditoren pivoxil Cephalosporins can be dissolved out faster.Meanwhile this hair
Any wetting agent (water) is not added for bright Cefditoren pivoxil Cephalosporins composition, Cefditoren pivoxil Cephalosporins crystal form in the case of avoiding wetting agent from existing
Conversion, thus ensure that effective component faster dissolution (Cefditoren pivoxil Cephalosporins once be converted into crystal form by unformed, dissolution
To be greatly reduced), while the stability of product is also improved, it reduces and turns the raw risk of trichite.
Preferably, the Cefditoren pivoxil Cephalosporins composition, in parts by weight, comprising:
Wherein, the water content of the unformed Cefditoren pivoxil Cephalosporins is less than 1%.
The preferred Cefditoren pivoxil Cephalosporins composition of institute, tabletting effect is more preferable, and each component synergistic effect improves production in formula
The stability of product avoids the transformation of crystal of unformed Cefditoren pivoxil Cephalosporins, guarantees the Fast Stripping of effective component.
The unformed Cefditoren pivoxil Cephalosporins is that (water content refers to that water quality accounts for nothing in unformed Cefditoren pivoxil Cephalosporins to water content
The percentage for Cefditoren pivoxil Cephalosporins gross mass of being formed) it is 1.0% unformed Cefditoren pivoxil Cephalosporins below, that is to say, that without fixed
Type Cefditoren pivoxil Cephalosporins can be entirely free of water, i.e., unformed Cefditoren pivoxil Cephalosporins is 0%, can greatly inhibit unformed cephalo
The transformation of appropriate logical sequence pivoxil crystal form, but it is very high to preparation process requirement, while production efficiency also decreases.Preferably, aqueous
Amount is the unformed Cefditoren pivoxil Cephalosporins of 0.5%-1.0%, facilitates production to prepare Cefditoren pivoxil Cephalosporins piece, while can guarantee institute
Effective component in Cefditoren pivoxil Cephalosporins piece is prepared being capable of Fast Stripping.And when the water content of unformed Cefditoren pivoxil Cephalosporins is super
1% is crossed, then is easy to happen the transformation of crystal of unformed Cefditoren pivoxil Cephalosporins, effective component dissolution is caused to reduce.
Preferably, the filler is microcrystalline cellulose, dicalcium phosphate dihydrate, pregelatinized starch, mannitol, two water
One of calcium sulfate is a variety of.Microcrystalline cellulose is widely used in pharmaceutical preparation, is mainly used as in oral tablet and capsule
Diluent and adhesive, cannot be only used for wet granulation can also be used for dry method direct tablet compressing.It is highly preferred that the microcrystalline cellulose
For microcrystalline cellulose 102, the microcrystalline cellulose 102 has greater particle size, suitable for the film-making of direct tablet compressing method, has good
Good mobility and compressibility.
Further, filler described in the Cefditoren pivoxil Cephalosporins composition includes the first auxiliary material and the second auxiliary material；
First auxiliary material is one or both of microcrystalline cellulose, pregelatinized starch；Second auxiliary material is two water of calcium monohydrogen phosphate
Close one of object, mannitol, calcium sulphate dihydrate or a variety of.Filler in the present invention is that two kinds of auxiliary materials play filling work jointly
With by taking microcrystalline cellulose 102 and dicalcium phosphate dihydrate as an example, microcrystalline cellulose 102 is filler, main to play filling work
With, while also playing certain calving disaggregation；Dicalcium phosphate dihydrate has good compressibility, is a kind of good filling
Agent, diluent are suitable for powder vertical compression technique, but its binding force is stronger, is not easy to disperse, and dosage should not be too big.Microcrystalline cellulose
102 are used in combination with dicalcium phosphate dihydrate, on the one hand play two kinds of respective advantages of auxiliary material, dicalcium phosphate dihydrate tool
There is good compressibility, but it does not absorb water, in water not easy disintegrating, microcrystalline cellulose 102, compressibility is general, after compressing
Fiber has good transmissibility after meeting water, disintegrating agent fast onset can be promoted to be disintegrated rapidly by moisture importing tablet core inner
Effect, while microcrystalline cellulose 102 itself also has certain calving disaggregation.By groping, microcrystalline cellulose 102 and phosphoric acid hydrogen
When calcium dihydrate is used in combination, the former dosage should be greater than the latter, general microcrystalline cellulose 102 and dicalcium phosphate dihydrate
Ratio be 1:0.6~0.9, be preferably in a proportion of 0.72~0.8.
In the present invention, microcrystalline cellulose 102 and dicalcium phosphate dihydrate are currently preferred filler, but of the invention
Filler be not limited to this two kinds of auxiliary materials.Specifically, microcrystalline cellulose can be replaced with pregelatinized starch, two water of calcium monohydrogen phosphate
Closing object can be replaced with mannitol, calcium sulphate dihydrate.
Preferably, the disintegrating agent is pregelatinized starch, croscarmellose sodium, carboxyrnethyl starch sodium, crosslinking carboxylic first
One of base cellulose calcium is a variety of.It that is to say, pregelatinized starch, croscarmellose sodium in the present invention, pregelatinated
Starch may be used alone, can also be used in combination with croscarmellose sodium.It is highly preferred that the disintegrating agent is pregelatinated
The mixture of starch and croscarmellose sodium, the ratio that the two is used in mixed way are 1:0.7~1.0.
Preferably, the lubricant is stearic acid, in magnesium stearate, calcium stearate, sodium stearyl fumarate, rilanit special
It is one or more.The lubricant makes the Cefditoren pivoxil Cephalosporins composition of preparation have good mobility and compressibility.More
Preferably, the lubricant is magnesium stearate.
The present invention also provides a kind of Cefditoren pivoxil Cephalosporins pieces, are made of label and coatings, wherein label includes institute as above
State Cefditoren pivoxil Cephalosporins composition.
The coatings are made of common coating material, such as pharmaceutical films are coated premixing auxiliary material.Preferably, the packet
Clothing layer is gastric solubility coatings.Specifically, the coatings include polyethylene glycol, hydroxypropyl methylcellulose, titanium dioxide and pigment.
The pigment is addition pigment commonly used in the art.The coating weight gain control of Cefditoren pivoxil Cephalosporins piece of the present invention 2.5%~
4%, preferred coating weight gain control range is 3%~4%.
Another aspect of the present invention additionally provides a kind of preparation method of Cefditoren pivoxil Cephalosporins piece, including unformed cephalo is appropriate
The supplementary materials such as logical sequence pivoxil carry out pulverize and sieve Deng pre-treatments, other auxiliary materials in addition to lubricant are mixed, and is done
It is dry, then the mixture of the raw material handled well and filler, disintegrating agent is premixed, lubricant is then added and carries out total mix,
Material sampling carries out intermediate products detection after total mix, according to the content of intermediate products, calculates theoretical loading amount, carries out tabletting, tabletting
Plain piece afterwards is coated, and obtains Cefditoren pivoxil Cephalosporins piece.
The preparation process of Cefditoren pivoxil Cephalosporins piece of the present invention is powder vertical compression technique, is generallyd use with the product wet
Method granulation, tablet forming technique are compared, and processing step is simple, without wet granulation and drying process, moisture in easily controllable preparation
Content, thus crystal form in easily controllable production process；Process is simple simultaneously, and energy consumption is lower, and the limiting factor of batch is less, is easy to
Large-scale industrial production.While simplifying preparation process, prepared Cefditoren pivoxil Cephalosporins piece and wet granulation, tabletting are made
Standby Cefditoren pivoxil Cephalosporins flake products dissolved corrosion is similar, other quality index also comply with standard requirements, and quality and original grind product
Unanimously.
The medicinal crystal-form of Cefditoren pivoxil Cephalosporins is unformed, but unformed Cefditoren pivoxil Cephalosporins is unstable, is existed in water
The case where translate into the Cefditoren pivoxil Cephalosporins of crystal form, how to control the moisture in production and preparation, be to maintain cefoperon
The unformed key of ester；In the prior art, wet granulation, the tablet forming technique generallyd use prepares Cefditoren pivoxil Cephalosporins piece, wet process
It joined wetting agent water in pelletization, need to be dried after granulation, but due to including that hygroscopicity is stronger in the material of granulation
Auxiliary material (more all generally there is water imbibition comprising filler, disintegrating agent etc.), be unfavorable for the removal of moisture, such situation
Under in order to achieve the purpose that it is as much as possible remove moisture removal, mostly use and realized by extending drying time, but with it is dry when
Between extension, the impurity in preparation will increase, and cause product total quality that will decline.
Cefditoren pivoxil Cephalosporins piece prepared by the present invention and original, which grind product, has similar dissolution feature, while formula composition
And simple production process, production process is easily controllable, and the crystal form of raw material will not be destroyed in production process, and any bonding is not added
The medicament containing moisture such as agent, wetting agent the removal dissolving agent process such as does not heat, effectively protects active constituent, be conducive to
Improve the stability of product.
Specific step is as follows for Cefditoren pivoxil Cephalosporins piece preparation method of the present invention:
Step 1: unformed Cefditoren pivoxil Cephalosporins is dried, in drying process control temperature of charge at 50 DEG C hereinafter,
Material moisture control is 1.0% hereinafter, controlling the material time for exposure in drying process within 10min after control is dry；
Step 2: unformed Cefditoren pivoxil Cephalosporins raw material being crushed, 80 meshes, smashed Material control D90 are crossed
(D90: particulate accumulation is distributed as 90% partial size, i.e., accounts for the 90% of whole particles less than the volumetric solid concentration of this partial size) is 20
~60 μm, the material time for exposure is controlled in 10min；Equally it is sieved to unclassified stores (filler, disintegrating agent, lubricant), mistake
Material is without agglomeration after sieve；
Step 3: weighing stock is carried out to unformed Cefditoren pivoxil Cephalosporins, filler, disintegrating agent, lubricant according to formula,
Wherein, the time for exposure is controlled when weighing unformed Cefditoren pivoxil Cephalosporins in 10min, controls envionmental humidity during weighing
Below 45%；
Step 4: the unclassified stores (filler, disintegrating agent) except unformed Cefditoren pivoxil Cephalosporins, lubricant is mixed
It closes, is dried after mixing, obtain mixed accessories, control temperature of charge is at 50~60 DEG C in drying, dry duration 1~2
Hour；
Step 5: the resulting material of step 4 being mixed with the resulting unformed Cefditoren pivoxil Cephalosporins of step 3, is obtained pre-
Material is mixed, pays attention to the control time for exposure within 10min in mixed process；
Step 6: step 5 resulting material being mixed with lubricant, obtains mixed material；
Step 7: tabletting being carried out using the resulting mixed material of step 6, obtains Cefditoren pivoxil Cephalosporins piece plain piece；
Step 8: being coated using the resulting plain piece of step 7, control coating weight gain 2.5~4%.
The characteristics of above-mentioned preparation process, is
Unformed Cefditoren pivoxil Cephalosporins is dried, control moisture 1.0% hereinafter, control moisture purpose be for
Unformed Cefditoren pivoxil Cephalosporins is prevented to be converted into the Cefditoren pivoxil Cephalosporins of crystal form；Temperature of charge is controlled in drying process at 50 DEG C
Hereinafter, having an impact hereinafter, having no to Cefditoren pivoxil Cephalosporins quality in the temperature, have no that impurity is significantly increased, it is preferred dry
Dry temperature is 45-50 DEG C；Drying mode can be common fluidized drying, oven drying etc., no matter which kind of drying mode be used,
Need to control exposure duration of the material in light no more than 10min, it is dry after material take the multi-layer sealed modes such as packed
It saves, guards against damp；
Pulverizing process in step 2 needs to control temperature of charge and exists at 50 DEG C hereinafter, controlling envionmental humidity simultaneously
45% or less；The D90 of comminuting matter is controlled controls the time for exposure in 10min in 20-60 μm, operating process；
Mixing described in step 4 can be multinomial movement mixer mixing, agitating paddle mixing, do described in step 3
Dry mode can be common fluidized drying, oven drying etc., duration 1-2 hours dry, and the material after drying takes multilayer close
The modes such as envelope dress save, and guard against damp；
Multinomial movement mixer mixing is mixed into described in step 5, mixing machine revolving speed is controlled at 12 ± 1 revs/min, mixed
Time 30-40min is closed, controls envionmental humidity 45% simultaneously in mixed process hereinafter, when controlling exposure in operating process
Between in 10min；
Multinomial movement mixer mixing is mixed into described in step 6, mixing machine revolving speed is controlled at 12 ± 1 revs/min, mixed
Time 30-40min is closed, controls envionmental humidity below 45% simultaneously in mixed process；
For the pressure that tabletting uses in step 7 for 6-12kg, preferred pressure is 8-11kg, controls environment phase in tableting processes
To humidity below 45%；
For Cefditoren pivoxil Cephalosporins raw material to light sensitive, light will cause the reduction of active component content, thus step 6 it
Before, control time≤40min that unformed Cefditoren pivoxil Cephalosporins is exposed under light；Envionmental humidity is controlled in preparation process
45% hereinafter, 22 ± 2 DEG C of environment temperature.
Embodiment below is only used for the more detailed description present invention, is not limitation of the present invention:
Embodiment 1: Cefditoren pivoxil Cephalosporins piece is (using microcrystalline cellulose and dicalcium phosphate dihydrate as filler, pregelatinated
Starch is disintegrating agent)
Yield: 1000 specifications: 100mg
Preparation process:
Unformed Cefditoren pivoxil Cephalosporins is dried, is then crushed, cross 80 meshes (D90 control 20-60 μm it
Between), each auxiliary material is controlled without agglomeration (crossing 80 meshes)；Unformed Cefditoren pivoxil Cephalosporins, microcrystalline cellulose, phosphorus are weighed according to formula ratio
Sour hydrogen calcium dihydrate, pregelatinized starch, magnesium stearate；Microcrystalline cellulose, dicalcium phosphate dihydrate, pregelatinized starch are thrown
Enter in mixing machine and mixed, material is dried after mixing；Microcrystalline cellulose, dicalcium phosphate dihydrate, pre- glue after drying
Change starch mixture to be mixed with smashed Cefditoren pivoxil Cephalosporins, mix 12 revs/min of revolving speed, incorporation time 30min, mixes
Magnesium stearate is added after the completion of closing and carries out total mix, mixes 12 revs/min of revolving speed, incorporation time 30min；Material sampling inspection after mixing
Content is surveyed, theoretical loading amount is calculated according to institute's measured data and carries out tabletting, controls 6~12kg of pressure；Gained plain piece is coated, control
Label weight gain 3%~4%, after packaging Cefditoren pivoxil Cephalosporins piece.
Embodiment 2: Cefditoren pivoxil Cephalosporins piece is (using microcrystalline cellulose and mannitol as filler, cross-linked carboxymethyl cellulose
Sodium is disintegrating agent)
Yield: 1000 specifications: 100mg
Preparation process:
Unformed Cefditoren pivoxil Cephalosporins is dried, is then crushed, cross 80 meshes (D90 control 30-60 μm it
Between), each auxiliary material is controlled without agglomeration (crossing 80 meshes)；Unformed Cefditoren pivoxil Cephalosporins, microcrystalline cellulose, sweet is weighed according to formula ratio
Reveal alcohol, croscarmellose sodium, magnesium stearate；Microcrystalline cellulose, mannitol, croscarmellose sodium investment is mixed
It is mixed in conjunction machine, material is dried after mixing；Microcrystalline cellulose, mannitol, croscarmellose sodium after drying
Mixture is mixed with smashed unformed Cefditoren pivoxil Cephalosporins, mixes 11 revs/min of revolving speed, incorporation time 40min, is mixed
Magnesium stearate is added after the completion of closing and carries out total mix, mixes 11 revs/min of revolving speed, incorporation time 40min；Material sampling inspection after mixing
Content is surveyed, theoretical loading amount is calculated according to institute's measured data and carries out tabletting, controls 7~11kg of pressure；Gained plain piece is coated, control
Label weight gain 2.5%~3.5%, after packaging Cefditoren pivoxil Cephalosporins piece.
Embodiment 3: Cefditoren pivoxil Cephalosporins piece is (using microcrystalline cellulose and mannitol as filler, pregelatinized starch and crosslinking
Sodium carboxymethylcellulose is disintegrating agent, stearic acid is lubricant)
Yield: 1000 specifications: 100mg
Preparation process:
Unformed Cefditoren pivoxil Cephalosporins is dried, is then crushed, cross 80 meshes (D90 control 20-40 μm it
Between), each auxiliary material is controlled without agglomeration (crossing 80 meshes)；Unformed Cefditoren pivoxil Cephalosporins, microcrystalline cellulose, sweet is weighed according to formula ratio
Reveal alcohol, pregelatinized starch, croscarmellose sodium, magnesium stearate；By microcrystalline cellulose, mannitol, pregelatinized starch, friendship
It is mixed in connection sodium carboxymethylcellulose investment mixing machine, material is dried after mixing；Microcrystalline cellulose, sweet dew after drying
Alcohol, pregelatinized starch, croscarmellose sodium mixture are mixed with smashed Cefditoren pivoxil Cephalosporins, mix revolving speed
13 revs/min, incorporation time 30min, magnesium stearate is added after the completion of mixing and carries out total mix, mixes 13 revs/min of revolving speed, mixing
Time 30min；Material sample detection content after mixing calculates theoretical loading amount according to institute's measured data and carries out tabletting, and pressure 8~
12kg；Gained plain piece is coated, control label weight gain 3%~4%, obtains Cefditoren pivoxil Cephalosporins piece after packaging.
By sample prepared in the above embodiments, to grind product (trade name " like to be beautiful gram ") molten in pH1.2 hydrochloric acid with original has been listed
Liquid, pH6.8 phosphate buffer, has carried out dissolution test in purified water at pH4.0 acetate buffer, as a result as follows:
The dissolution comparing result (unit: %) of table 1:pH1.2 hydrochloric acid solution
In table 1, in pH1.2 hydrochloric acid solution, by sample prepared by the present invention, to grind dissolution of the product in 15min big with original
In 85%, all extremely fast to dissolve out, it is similar that the sample of each embodiment preparation to original grinds product dissolved corrosion.
The dissolution comparing result (%) of table 2:pH4.0 acetum
| Original grinds product | Embodiment 1 | Embodiment 2 | Embodiment 3 | |
| 0 | 0 | 0 | 0 | 0 |
| 5min | 13 | 15 | 16 | 19 |
| 10min | 24 | 22 | 24 | 29 |
| 15min | 27 | 28 | 29 | 36 |
| 20 | 29 | 29 | 32 | 40 |
| 30 | 33 | 32 | 36 | 42 |
| 45 | 36 | 34 | 38 | 45 |
| 60 | 38 | 37 | 39 | 46 |
| 90 | 39 | 40 | 42 | 47 |
| Batch f2 value is ground with original* | / | 88 | 79 | 54 |
In table 2, f2 value is the whether similar data of two kinds of sample dissolved corrosions of evaluation, under normal circumstances, when f2 value is not small
When 50, it is believed that dissolution curve is similar.
The dissolution comparing result (%) of table 3:pH6.8 acetum
| Original grinds product | Embodiment 1 | Embodiment 2 | Embodiment 3 | |
| 0 | 0 | 0 | 0 | 0 |
| 5min | 13 | 12 | 13 | 15 |
| 10min | 24 | 22 | 21 | 24 |
| 15min | 27 | 25 | 26 | 29 |
| 20 | 29 | 27 | 28 | 34 |
| 30 | 33 | 35 | 32 | 35 |
| 45 | 36 | 36 | 33 | 38 |
| 60 | 38 | 38 | 35 | 40 |
| 90 | 39 | 39 | 36 | 45 |
| Batch f2 value is ground with original | / | 88 | 97 | 66 |
Table 4: the dissolution comparing result (%) in purified water
Delay in solution, pH6.8 phosphate buffer solution and purified water in pH4.0 acetate, the f2 value of each sample is all larger than
50, the dissolution curve for grinding product with original has similitude.
The sample of 1-3 of embodiment of the present invention preparation and the former Key Quality attribute for grinding product have carried out investigating comparison, as a result
It is as follows:
Table 5: embodiment sample and original grind the comparison of product Key Quality attribute
The above comparative study the result shows that: the sample and original of each embodiment preparation grind product with similar impurity spectrum, implementation
Example prepares the impurity content of sample in bound requirements.
Using accelerated test condition (temperature: 40 DEG C ± 2 DEG C, humidity: 75% ± 5%) to embodiment 2, embodiment 3 and former
It grinds product and has carried out 6 months study on the stability, it is as follows that key index investigates result:
Table 6: Key Quality Indicator stability test data
In table 6, " " indicate to be not detected.
Stability test the result shows that, the stability and original of embodiment sample, which are ground, does not have notable difference between product, each miscellaneous
The content of matter is less than bound requirements.(bound requirements of each impurity are referring to the former import registered standard and newest ICH for grinding product
Member state's pharmacopeia is worked out).
From brilliant condition analysis is turned, water content is lower, is more conducive to the stabilization of unformed Cefditoren pivoxil Cephalosporins.The present invention couple
The stabilization of unformed Cefditoren pivoxil Cephalosporins that water content is 1.0% is also investigated, investigate the result shows that, when moisture control exists
When 1.0%, stable product quality is preferable, and specific data is shown in Table 7.
The stability test data for the unformed Cefditoren pivoxil Cephalosporins that 7 water content of table is 1.0%
In table 7, the storage condition of refrigeration and the unformed Cefditoren pivoxil Cephalosporins of freezing expression, " " indicate to be not detected.
It should be understood that the application of the present invention is not limited to the above for those of ordinary skills can
With improvement or transformation based on the above description, all these modifications and variations all should belong to the guarantor of appended claims of the present invention
Protect range.
Claims (10)
1. a kind of preparation method of the appropriate logical sequence pivoxil plain piece of spore, which is characterized in that comprising steps of
Unformed Cefditoren pivoxil Cephalosporins is dried, the water content of the unformed Cefditoren pivoxil Cephalosporins after control is dry is less than
1%；
Filler, disintegrating agent, lubricant are mixed with the unformed Cefditoren pivoxil Cephalosporins after drying, obtain mixed material；
The mixed material is subjected to tabletting, obtains Cefditoren pivoxil Cephalosporins plain piece.
2. the preparation method of the appropriate logical sequence pivoxil plain piece of spore according to claim 1, which is characterized in that it is described by filler, collapse
Solution agent, lubricant mix specifically including with the unformed Cefditoren pivoxil Cephalosporins after drying:
Filler is mixed with disintegrating agent, obtains mixed accessories；
The mixed accessories are mixed with the unformed Cefditoren pivoxil Cephalosporins after drying, obtain premix material；
The premix material is mixed with lubricant, obtains mixed material.
3. the preparation method of the appropriate logical sequence pivoxil plain piece of spore according to claim 1 to 2, which is characterized in that the filler
One of microcrystalline cellulose, pregelatinized starch, dicalcium phosphate dihydrate, mannitol, calcium sulphate dihydrate.
4. the preparation method of the appropriate logical sequence pivoxil plain piece of spore according to claim 1 to 2, which is characterized in that the disintegrating agent
One of pregelatinized starch, croscarmellose sodium, carboxyrnethyl starch sodium, cross-linked carboxymethyl cellulose calcium are a variety of.
5. the preparation method of the appropriate logical sequence pivoxil plain piece of spore according to claim 1 to 2, which is characterized in that the lubricant
For one of stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, rilanit special or a variety of.
6. the preparation method of the appropriate logical sequence pivoxil plain piece of spore according to claim 1, which is characterized in that described to unformed cephalo
The drying temperature that appropriate logical sequence pivoxil is dried is 50 DEG C or less.
7. the preparation method of the appropriate logical sequence pivoxil plain piece of spore according to claim 1, which is characterized in that described to unformed head
It further include that pulverization process is carried out to the unformed Cefditoren pivoxil Cephalosporins after drying after the appropriate logical sequence pivoxil of spore is dried.
8. a kind of appropriate logical sequence pivoxil plain piece of spore, which is characterized in that using the appropriate logical sequence pivoxil plain piece of the spore as described in claim 1-7 is any
Preparation method is prepared.
9. a kind of preparation method of the appropriate logical sequence pivoxil piece of spore, which is characterized in that by the appropriate logical sequence pivoxil plain piece of spore as claimed in claim 8 into
Row coating, is prepared the appropriate logical sequence pivoxil piece of spore.
10. a kind of appropriate logical sequence pivoxil piece of spore, which is characterized in that using the preparation method of the appropriate logical sequence pivoxil piece of spore as claimed in claim 9
It is prepared.
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| CN112315930A (en) * | 2020-11-10 | 2021-02-05 | 深圳立健药业有限公司 | Cefditoren pivoxil tablet and preparation method thereof |
| CN117731649A (en) * | 2023-12-21 | 2024-03-22 | 博济医药科技股份有限公司 | Tranexamic acid pharmaceutical composition and preparation process thereof |
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