CN105796521B - Improved Amoxicillin delayed release formulation - Google Patents
Improved Amoxicillin delayed release formulation Download PDFInfo
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- CN105796521B CN105796521B CN201610137731.XA CN201610137731A CN105796521B CN 105796521 B CN105796521 B CN 105796521B CN 201610137731 A CN201610137731 A CN 201610137731A CN 105796521 B CN105796521 B CN 105796521B
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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
- A61K9/2004—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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- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/429—Thiazoles condensed with heterocyclic ring systems
- A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
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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
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—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 belongs to Amoxicillin delayed release formulation technical fields, and in particular to a kind of composition of amoxicillin tablets and preparation method thereof with pulsatile release characteristics.The present invention is directed to existing releasing rate of prepared amoxycillin sustained release tablet（MOXATAG®）It is improved, preparation takes after can disperseing piece in water in advance and remains to holding and MOXATAG®The amoxicillin tablets of 3 consistent pulse releases of release characteristics.The piece solves MOXATAG®Need full wafer to swallow, patient's dysphagia leads to the problem of Compliance difference, while overcoming thin membrane coated tablet MOXATAG®The problems such as being directly changed to bad mouthfeel caused by target patch, bad stability, inconsistent dissolution characteristic by former technology, according to amoxicillin tablets prepared by the present invention, convenient to take, mouthfeel is good, and stability is better than MOXATAG®, dissolution characteristic and MOXATAG®Unanimously.
Description
Technical field
The invention belongs to Amoxicillin delayed release formulation technical fields, and in particular to a kind of Ah not with pulsatile release characteristics
The composition and preparation method thereof of XiLin piece.
Background technology
Amoxicillin is a kind of wide spectrum beta-lactam antibiotic, and bactericidal effect is strong, and the ability of penetration cell wall is also strong,
It is one of current widely used oral penicillin.The medicine pharmacokinetics feature be gastrointestinal absorption is rapid, metabolism is fast, effect when
Between it is short, belong to Time dependence antibiotic i.e. antibacterial effect depend on T>The time of MIC (minimal inhibitory concentration) rather than concentration.So
And found in prolonged clinical practice, the medicining mode (4 times a day a, 250mg) of Amoxicillin ordinary preparation is significantly
The compliance of patient medication is reduced, drug resistance phenomenon is more and more, and adverse reaction rate is also higher and higher.In January, 2008,
FDA ratifies New-type long-acting multiple-pulse tablet formulation-releasing rate of prepared amoxycillin sustained release tablet (775mg/ days) of Middlebrook companies in U.S.
State lists, trade nameIt is the daily primary long-acting multiple-pulse piece in current whole world only one Amoxicillin
Agent formulation.Said preparation uses pulsed release technical controlling drug different parts sustained release in gastrointestinal tract, after taking, the first arteries and veins
It rushes particle to be disintegrated rapidly in gastric juice, blood concentration is rapidly reached MIC or more, as drug operates in the gastrointestinal tract, in physiology
Under environmental activity, second, third impulse pellet gradually starts to discharge drug, and maintains blood concentration in the time of MIC or more, and one
Aspect achievees the purpose that pulse, on the other hand maintains long-acting effect again.Clinical test proves, said preparation and daily medication 4 times
Ordinary preparation it is suitable compared to validity, but times for spraying greatly reduces, while dosage reduces, and obtains filling for clinical expert
Divide affirmative, this is also the medically approval to Amoxicillin durative action preparation for the first time.
Piece specification is 775mg (it is 891.2mg to be equivalent to Utimox), and contains 3 kinds of pulses
Medicine-releasing system, therefore every piece is up to 1.5g again, chip size (length × width x thickness) is about 22mm × 10mm × 8mm, considerably beyond state
The size of interior Coming-of-Age Day informal dress piece, andIt needs full wafer to swallow when taking, not can be chewed or bite into pieces, piece type
It is larger, all dysphagias, needless to say adolescent patient, gerontal patient and the trouble for having dysphagia for adult patient
Person.It is outstanding that deficiency in above-mentioned medication strongly limits clinical advantagePopularization and application clinically at home,
To improve the compliance of domestic patient's medication, treatment advantage of the pulsed release compared with ordinary preparation antibacterial is played, it is necessary to rightIt is improved.It willThe tablet for being modified to take again after can in advance in water disperseing more directly gulps down
The compliance of patient's medication can be greatly improved in the thin membrane coated tablet of clothes, but willTarget is changed to by thin membrane coated tablet
There are following challenges for the formulation scientist of this field for piece：
1. being taken after need to disperseing in water because of target patch, so cannot be coated, and require the piece in the case where not being coated
Medicine stability cannot be inferior to existing for film coating sheet form
②Middle pulse 1 is Amoxicillin immediate-release granules, when target patch is made with the particle shape of pulse 1
When, since target patch can be disintegrated into rapidly particle or pellet in water, produced by the Amoxicillin that immediate-release granules dissolve out in water
Bitter taste the stop of long period is had in mouth, be unfavorable for the compliance of patient's medication, need pairIn pulse
1 particle is improved to improve the mouthfeel of target patch；
③Middle pulse 2 is methacrylic acid and ethyl acrylate 1:The dispersion of 1 copolymer
The enteric-coated micro-pill of (Eudragit L30D-55) coating, pulse 3 are hydroxypropyl methylcellulose acetate succinate (AQOAT AS-HF)
The enteric-coated micro-pill of coating.Methacrylic acid and ethyl acrylate 1:1 copolymer and hydroxypropyl methylcellulose acetate succinate AS-
HF types are pH value dependence enteric-coating material, and it is respectively >=5.5 and >=6.5 that film, which dissolves pH value, and China's Drinking Water is defended
The pH value of regulation Drinking Water for Residents is between 6.5~8.5 in raw standard, when directly withMiddle pulse 2 and pulse 3
When target patch is made in composition, the film due to PH value of drinking water higher than Eudragit L30D-55 and AQOAT AS-HF dissolves pH value,
The film clothing of pulse 2 and pulse 3, which has different degrees of dissolving, causes the even dosage of release in advance of drug in capsule core to come down in torrents, because
This, the dissolution characteristic of target patch can be withIt is inconsistent, to influence the bioavilability of drug in vivo and then shadow
When ringing efficacy and saferry, therefore target patch be made, need pairIn pulse 2 and pulse 3 be improved, keep its molten
Go out characteristic withUnanimously.
Invention content
The present invention is directed to existing releasing rate of prepared amoxycillin sustained release tabletIt is improved, preparation can be advance by piece
In water disperse after take and remain to keep withThe amoxicillin tablets of 3 consistent pulse releases of release characteristics.It should
Piece solvesNeed full wafer to swallow, patient's dysphagia leads to the problem of Compliance difference, while overcoming thin
Film coating pieceIt is directly changed to bad mouthfeel caused by target patch, bad stability, dissolution characteristic by former technology
The problems such as inconsistent, according to amoxicillin tablets prepared by the present invention, convenient to take, mouthfeel is good, and stability is better thanDissolution characteristic withUnanimously.
The present invention is intended to provide a kind of improved amoxicillin tablets, it is characterised in that the piece is by 1 pellet of pulse, pulse 2
Tabletting is made after mixing with pharmaceutically acceptable excipient for pellet, 3 pellet of pulse；Active constituent in 1 pellet of pulse
Dosage accounts for the 45% of every middle active constituent accumulated dose, and it is total that the active constituent dosage in 2 pellet of pulse accounts for every middle active constituent
The 30% of dosage, the active constituent dosage in 3 pellet of pulse account for the 25% of every middle active constituent accumulated dose；1 pellet of pulse by
It is interior and outer be made of successively Amoxicillin capsule core, separation layer and coatings soluble in the stomach；2 pellet of pulse is from inside to outside successively by A Moxi
Woods capsule core, enteric coat layer and coatings soluble in the stomach are constituted；3 pellet of pulse is from inside to outside successively by Amoxicillin capsule core, enteric packet
Clothing layer and coatings soluble in the stomach are constituted, and the filmogen of the coatings soluble in the stomach in 3 pellet of pulse 1, pulse 2 and pulse is selected from methyl
Methyl acrylate and diethyl amino ethyl group methacrylate 7:3 copolymer or methyl methacrylate and diethyl amino ethyl group methyl
Acrylate 7:30% aqueous dispersion of 3 copolymer.
Methyl methacrylate and diethyl amino ethyl group methacrylate 7:3 copolymer or its 30% aqueous dispersion are formed
Film clothing have and dissolved in pH5.5 or less solution, the undissolved characteristic in pH5.5 or more solution.It is 30% water-dispersed at it
Further include lauryl sodium sulfate etc. in addition to the copolymer of methyl methacrylate and diethyl amino ethyl group methacrylate in body
As stabilizer.Methyl methacrylate and diethyl amino ethyl group methacrylate 7 in the present invention:3 copolymer or its
30% aqueous dispersion is the filmogen of the outermost clothing layer soluble in the stomach of 1,2,3 pellet of pulse, on the one hand protects 1,2,3 pellet of pulse
The integrality of internal layer separation layer or enteric coating layer when disperseing in water will not cause drug to be released or take in water because film clothing dissolves
The gastrointestinal tract of certain ph does not discharge and discharges dosage is caused to come down in torrents in advance in vivo after, and one side patient takes liquid and enters body
After interior, outermost clothing layer soluble in the stomach can dissolve rapidly in the gastric juice environment of low ph value should be in stomach without influencing pulse 1,2,3
The dissolution characteristic of enteron aisle specific pH stage pulses release, to ensure the dissolution characteristic of target patch in vitro with
Unanimously, i.e., withPulse 1 discharged in the gastric juice of pH value≤4, pulse 2 discharges in the intestinal juice of pH value >=5.5
And pulse 3 discharges consistent dissolution characteristic in the intestinal juice of pH value >=6.5.Methyl methacrylate and diethyl amino ethyl group methyl-prop
Olefin(e) acid ester 7:The film clothing water vapour permeability that 3 copolymer or its 30% aqueous dispersion are formed is low, and humidity resistance is more excellent, the present invention
Although the tabletted rear piece of 1,2,3 pellet of pulse in is uncoated, and stability is better than film coating
Better than useTechnology prepare the pulse 1 ' by not wrapping clothing layer soluble in the stomach, pulse 2 ' and 3 ' pellet of pulse and its
Amoxicillin tablets made of his suitable excipient is suppressed after mixing.
The filmogen of enteric coat layer in 2 pellet of the pulse is selected from methacrylic acid and ethyl acrylate 1:1
The filmogen of copolymer or its 30% aqueous dispersion, the enteric coat layer in 3 pellet of the pulse is selected from hydroxypropyl methylcellulose
Acetate succinate AS-HF types.
The composition of 1 pellet of the pulse is as follows：
(1) Amoxicillin capsule core：The percentage that each ingredient accounts for Amoxicillin capsule core gross weight is as follows：
(2) separation layer：The percentage that each ingredient accounts for separation layer gross weight is as follows：
Filmogen 80%~95%
Plasticizer 5%~20%
Separation layer directly selects stomach dissolution typeFilm coating pre-mix dose, weightening：Separation layer weightening is Amoxicillin
The 4%~8% of capsule core gross weight；
(3) coatings soluble in the stomach：The percentage that each ingredient accounts for coatings gross weight soluble in the stomach is as follows：
Methyl methacrylate and diethyl amino ethyl group methacrylate 7:3 copolymer or its 30% aqueous dispersion, with
Polymer dry weight meter 60%~70%
Weightening：Coatings weightening soluble in the stomach is 4%~8% of the Amoxicillin capsule core gross weight comprising separation layer.
Diluent in the Amoxicillin capsule core composition is selected from microcrystalline cellulose or powdered cellulose, and adhesive is selected from hydroxyl
Third methylcellulose or hydroxypropylcellulose, wetting agent are selected from Emulsifier EL-35 or lauryl sodium sulfate；Separation layer forms
Middle filmogen is selected from hydroxypropyl methylcellulose or hydroxypropylcellulose or hydroxyethyl cellulose, and plasticizer is selected from glycerine, propylene glycol, gathers
It is any in ethylene glycol, triethyl citrate, triacetin, triacetyl glycerine, monoacetin；Coatings group soluble in the stomach
Cheng Zhong, plasticizer are selected from triethyl citrate, tributyl citrate, acetyl triethyl citrate/docusate sodium, acetyl tributyl citrate
Any in tributyl/docusate sodium, dibutyl sebacate/docusate sodium, antiplastering aid is selected from talcum powder, and antioxidant is selected from dibutyl
Hydroxy-methylbenzene, colorant are appointed in water colo(u)r, fat-soluble pigment, water-insoluble aluminum lake, titanium dioxide, iron oxides
One.
2 pellet of the pulse is made of Amoxicillin capsule core, enteric coat layer and coatings soluble in the stomach successively from inside to outside,
In, for the composition of Amoxicillin capsule core and coatings soluble in the stomach with 1 pellet of pulse, coatings weightening soluble in the stomach is to include enteric coating
The 4%~8% of the Amoxicillin capsule core gross weight of layer, and each ingredient accounts for the percentage of enteric coat layer gross weight such as in enteric coat layer
Under：
Methacrylic acid and ethyl acrylate 1:1 copolymer or its 30% aqueous dispersion, 50% in terms of polymer dry weight
~70%
Plasticizer 10%~25%
Antiplastering aid 15%~30%
2 pellet of above-mentioned pulse enteric coat layer composition in plasticizer be selected from polyethylene glycol, acetyl triethyl citrate,
It is any in triethyl citrate, antiplastering aid be selected from talcum powder, enteric coat layer weightening be Amoxicillin capsule core gross weight 15%~
20%.
3 pellet of the pulse is made of Amoxicillin capsule core, enteric coat layer and coatings soluble in the stomach successively from inside to outside,
In, for the composition of Amoxicillin capsule core and coatings soluble in the stomach with 1 pellet of pulse, coatings weightening soluble in the stomach is to include enteric coating
The 4%~8% of the Amoxicillin capsule core gross weight of layer, and each ingredient accounts for the percentage of enteric coat layer gross weight such as in enteric coat layer
Under：
Hydroxypropyl methylcellulose acetate succinate AS-HF types 50%~60%
Triethyl citrate 15%~25%
Talcum powder 20%~30%
Lauryl sodium sulfate 1%~3%
Weightening：Enteric coat layer weightening is the 20%~25% of Amoxicillin capsule core gross weight.
In the amoxicillin tablets Chinese pharmacology acceptable excipient be selected from diluent, adhesive, disintegrant, lubricant,
The combination of one or more of glidant, corrigent, the excipient can be in by the particle form of wet granulation, dry granulation
It is existing, or individually or in the form of powder mixes presented by powder；Wherein, diluent is selected from starch, microcrystalline cellulose, pregelatinated and forms sediment
It is any in powder, calcium monohydrogen phosphate, lactose, sucrose, sugar alcohol, preferably lactose, microcrystalline cellulose, pregelatinized starch；Adhesive is selected from hydroxyl
It is any in third methylcellulose, hydroxypropylcellulose, hydroxyethyl cellulose, polyvinylpyrrolidone, sodium carboxymethylcellulose, preferred hydroxyl
Third methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone；Disintegrant is selected from starch, pregelatinized starch, carboxyrnethyl starch sodium, hydroxyl
Any or microcrystalline cellulose, powdered cellulose, carboxymethyl cellulose, croscarmellose sodium, carboxymethyl in propyl starch
Any or crospovidone in cellulose calcium, preferably carboxyrnethyl starch sodium, croscarmellose sodium, crospovidone；Lubrication
Agent is selected from magnesium stearate or sodium stearyl fumarate；Glidant is selected from silica；Corrigent is selected from aspartame, acesulfame potassium, three
It is any in chlorine sucrose.
The preparation process of 1 pellet of the pulse is as follows：
(1) prepared by Amoxicillin capsule core
Adhesive and wetting agent are dissolved in the water, certain density binder solution is formed.By size controlling in 100 mesh
Amoxicillin below and diluent are placed in wet granulator and are uniformly mixed, and it is soft that binder solution system is added in mixed process
Material.Above-mentioned obtained softwood is placed in extruder and is squeezed out, collection extrusion item, which is placed in spheronizator, carries out round as a ball pelletization operation,
Capsule core of the collection cut size between the mesh of 30 mesh~60, spare after 40 DEG C~45 DEG C dryings；
(2) packet separation layer
By filmogen and plasticizer or directly by stomach dissolution typeFilm coating pre-mix dose is configured to wrap with suitable quantity of water
Amoxicillin capsule core is placed in fluid bed and is coated by clothing liquid, and separation layer weightening is the 4%~8% of Amoxicillin capsule core gross weight；
(3) clothing layer soluble in the stomach is wrapped
By methyl methacrylate and diethyl amino ethyl group methacrylate 7:30% aqueous dispersion of 3 copolymer resists
Stick, antioxidant, plasticizer, colorant are dispersed in water to form Coating Solution, and the Amoxicillin pellet for being surrounded by separation layer is set
Be coated in fluid bed, clothing layer soluble in the stomach weightening accounts for the 4%~8% of the pellet gross weight of Amoxicillin containing separation layer, after will coating gained
Pellet is dry at 40 DEG C~45 DEG C, and 40 DEG C~50 DEG C cure at least 24 hours.
The preparation process of 2 pellet of the pulse is as follows：
(1) prepared by Amoxicillin capsule core
It is prepared with pulse 1 pellet preparation process (1) Amoxicillin capsule core；
(2) enteric-coating layer
By methacrylic acid and ethyl acrylate 1:1 copolymer or its 30% aqueous dispersion, plasticizer, antiplastering aid are used suitable
Amount water is configured to coating solution, and Amoxicillin capsule core is placed in fluid bed and is coated, and enteric coating layer weightening is that Amoxicillin capsule core is total
The 15%~20% of weight, after coating micro-pill is dry at 40 DEG C~45 DEG C, 40 DEG C~50 DEG C cure at least 24 hours；
(2) clothing layer soluble in the stomach is wrapped
By methyl methacrylate and diethyl amino ethyl group methacrylate 7:30% aqueous dispersion of 3 copolymer resists
Stick, antioxidant, plasticizer, colorant are dispersed in water to form Coating Solution, will be surrounded by the Amoxicillin pellet of enteric coating layer
Be placed in fluid bed and be coated, clothing layer soluble in the stomach weightening accounts for the 4%~8% of the pellet gross weight of Amoxicillin containing enteric coating layer, after will coating
Gained pellet is dry at 40 DEG C~45 DEG C, and 40 DEG C~50 DEG C cure at least 24 hours.
The preparation process of 3 pellet of the pulse is as follows：
(1) prepared by Amoxicillin capsule core
It is prepared with pulse 1 pellet preparation process (1) Amoxicillin capsule core；
(2) enteric-coating layer
By hydroxypropyl methylcellulose acetate succinate AS-HF types, triethyl citrate, talcum powder, lauryl sodium sulfate
It is configured to coating solution with suitable quantity of water, Amoxicillin capsule core is placed in fluid bed and is coated, enteric coating layer weightening is Amoxicillin ball
The 20%~25% of core gross weight；
(3) clothing layer soluble in the stomach is wrapped
By methyl methacrylate and diethyl amino ethyl group methacrylate 7:30% aqueous dispersion of 3 copolymer resists
Stick, antioxidant, plasticizer, colorant are dispersed in water to form Coating Solution, will be surrounded by the Amoxicillin pellet of enteric coating layer
Be placed in fluid bed and be coated, clothing layer soluble in the stomach weightening accounts for the 4%~8% of the pellet gross weight of Amoxicillin containing enteric coating layer, after will coating
Gained pellet is dry at 40 DEG C~45 DEG C, and 40 DEG C~50 DEG C cure at least 24 hours.
The amoxicillin tablets the slurry processes of 2015 editions four 0,931 second law regulations of Chinese Pharmacopoeia, rotating speed 100rpm,
Dissolution medium is 900ml, medium temperature is 37 DEG C ± 0.5 DEG C, pH value be respectively 4.0,6.0 and 6.8 phosphate buffer in
Dissolution characteristic it is as follows：
| Dissolution time | Dissolution medium | Cumulative leaching rate |
| 15min | PH4.0 phosphate buffers | 35%~45% |
| 2h | PH4.0 phosphate buffers | 40%~50% |
| 2h15min | PH6.0 phosphate buffers | 65%~75% |
| 4h | PH6.0 phosphate buffers | 70%~80% |
| 4h15min | 6.8 phosphate buffers of pH | >=85% |
| 6h | 6.8 phosphate buffers of pH | >=90% |
Description of the drawings
Attached drawing 1：Make 19-22 sample of prescription and commercially available medicine by oneselfStripping curve comparison diagram
Attached drawing 2：Make 15-18 sample of prescription and commercially available medicine by oneselfStripping curve comparison diagram
Specific implementation mode
It further illustrates the present invention by the following examples, but does not limit invention content.
1 Amoxicillin capsule core of embodiment prepares (scale：1kg)
Preparation method：1. material pre-treatment：Amoxicillin size controlling in 100 mesh hereinafter, weigh hydroxypropyl methylcellulose or
Hydroxypropylcellulose is configured to 3% (w/w) aqueous solution, and Emulsifier EL-35 or lauryl sodium sulfate are added thereto, molten
Solution is uniformly rear spare.2. material mixes：It weighs in Amoxicillin, microcrystalline cellulose or powdered cellulose to mixing wet granulator
Mixing.3. softwood processed：Binder solution is added in above-mentioned material, softwood processed is stirred.4. extrusion spheronization：Above-mentioned softwood is placed in
It is squeezed out in extruder and (squeezes out screen distance：0.5mm), rate of extrusion is 25Hz~35Hz, collects extrusion item and is placed in spheronizator
Middle to carry out round as a ball pelletization operation, round as a ball rate is 1500r/m~2000r/m.5. pellet is dried：40 DEG C~45 DEG C dryings are to capsule core
Intermediate moisture≤15.0%, pellet of the rear collection cut size between the mesh of 30 mesh~60 are spare.
2 pulse of embodiment, 1 pellet preparation-Amoxicillin capsule core packet separation layer prepares (scale：1kg)
Preparation method：1. weighing hydroxypropyl methylcellulose, Macrogol 6000 or directly by commercially available film coating pre-mix dose stomach
Molten type It is dissolved or dispersed in appropriate aqueous solution and is made into coating solution, solid content about 15%.2. Amoxicillin capsule core is set
Be coated in fluidized-bed coating machine, leaving air temp is about 40~50 DEG C, separation layer weightening be about Amoxicillin capsule core gross weight 4~
8%.
3 pulse of embodiment, the 1 pellet preparation-Amoxicillin capsule core packet clothing layer soluble in the stomach containing separation layer prepares (scale：1kg)
Preparation method：1. weighing methyl methacrylate and diethyl amino ethyl group methacrylate 7:3 copolymer
30% aqueous dispersion, tributyl citrate or triethyl citrate, talcum powder, dibutyl hydroxy toluene or titanium dioxide are dispersed in
Coating Solution, solid content about 15%~20% are formed in water.2. the Amoxicillin pellet of separation layer will be surrounded by made from embodiment 2
It is placed in fluid bed and is coated, for leaving air temp about at 40 DEG C, clothing layer weightening soluble in the stomach, which accounts for, is surrounded by separation layer Amoxicillin pellet gross weight
4%~8%, after will coating gained pellet dry about 2 hours at 40 DEG C~45 DEG C, 40 DEG C~50 DEG C cure at least 24 hours.
4 pulse of embodiment, 2 pellet preparation-Amoxicillin capsule core enteric-coating layer prepares (scale：1kg)
Note：Eudragit L100-55 are methacrylic acid and ethyl acrylate 1:1 copolymer dry powder lists product,
Eudragit L30D-55 are containing methacrylic acid and ethyl acrylate 1:30% aqueous dispersion of 1 copolymer dry powder lists
Product.
Preparation method：1. weighing Eudragit L100-55 or Eudragit L30D-55, triethyl citrate or acetyl
Triethyl citrate, talcum powder disperse in the right amount of water to form coating solution, are coated fluid solid content about 10%.2. embodiment 1 is made
The Amoxicillin capsule core obtained is placed in fluid bed, adjusts about 32 DEG C of inlet air temperature, and about 25 DEG C of leaving air temp is coated, enteric coating
Layer weightening accounts for the 15%~20% of Amoxicillin pellet gross weight, after will coating gained pellet it is dry about 2 small at 40 DEG C~45 DEG C
When, 40 DEG C~50 DEG C cure at least 24 hours.
5 pulse of embodiment, the 2 pellet preparation-Amoxicillin capsule core packet clothing layer soluble in the stomach containing enteric coating layer prepares (scale：
1kg)
Preparation method：1. weighing methyl methacrylate and diethyl amino ethyl group methacrylate 7:3 copolymer
30% aqueous dispersion, acetyl triethyl citrate/docusate sodium or tributyl 2-acetylcitrate/docusate sodium, talcum powder dispersion
Coating Solution, solid content about 15%~20% are formed in suitable quantity of water.2. Ah not of enteric coating layer will be surrounded by made from embodiment 4
XiLin pellet, which is placed in fluid bed, to be coated, and about 55 DEG C of inlet air temperature is adjusted, and about 40 DEG C of leaving air temp is coated, and clothing layer soluble in the stomach increases
Account for the 4%~8% of the pellet gross weight of Amoxicillin containing enteric coating layer again, after will coating gained pellet at 40 DEG C~45 DEG C it is dry about
2 hours, 40 DEG C~50 DEG C cured at least 24 hours.
6 pulse of embodiment, 3 pellet preparation-Amoxicillin capsule core enteric-coating layer prepares (scale：1kg)
| Composition | 11 | Percentage | 12 | Percentage | Effect |
| Amoxicillin capsule core | 1000 | 83.3% | 1000 | 80% | Pellet core |
| Hydroxypropyl methylcellulose acetate succinate | 100 | 8.3% | 150 | 12% | Filmogen |
| Triethyl citrate | 50 | 4.2% | 40 | 3.2% | Plasticizer |
| Talcum powder | 44 | 3.7% | 57 | 4.6% | Antiplastering aid |
| Lauryl sodium sulfate | 6 | 0.5% | 3 | 0.2% | Stabilizer |
| Water | In right amount | - | In right amount | - | Coating solution solvent |
| It amounts to (g) | 1200 | 100% | 1250 | 100% | |
| Remarks | Capsule core is 1 | Capsule core is 2 |
Preparation method：1. weighing hydroxypropyl methylcellulose acetate succinate, triethyl citrate, talcum powder, dodecyl
Sodium sulphate disperses in the right amount of water to form coating solution, is coated fluid solid content about 5%.2. by enteric coating is contained made from embodiment 5
The Amoxicillin capsule core of layer is placed in fluid bed, adjusts about 40 DEG C of inlet air temperature, and about 30 DEG C of leaving air temp is coated, enteric coating
Layer weightening accounts for the 20%~25% of Amoxicillin pellet gross weight.
7 pulse of embodiment, the 3 pellet preparation-Amoxicillin capsule core packet clothing layer soluble in the stomach containing enteric coating layer prepares (scale：
1kg)
Preparation method：1. weighing methyl methacrylate and diethyl amino ethyl group methacrylate 7:3 copolymer
30% aqueous dispersion, dibutyl sebacate/docusate sodium or tributyl citrate, talcum powder, dibutyl hydroxy toluene are dispersed in
Coating solution is formed in suitable quantity of water, is coated fluid solid content about 15%~20%.2. by be surrounded by made from embodiment 6 enteric coating layer Ah
Amdinocillin pellet, which is placed in fluid bed, to be coated, and about 55 DEG C of inlet air temperature is adjusted, and about 40 DEG C of leaving air temp is coated, clothing layer soluble in the stomach
Weightening accounts for the 4%~8% of the pellet gross weight of Amoxicillin containing enteric coating layer, after will coating gained pellet it is dry at 40 DEG C~45 DEG C
About 2 hours, 40 DEG C~50 DEG C cured at least 24 hours.
8 amoxicillin tablets of embodiment prepare that (single dose composition is as shown in the table, unit：Mg prepares batch：5000
Piece)
Preparation method：Prescription 15-weighs pulse 1, pulse 2, pulse 3, microcrystalline cellulose, crospovidone, magnesium stearate, two
Silica tabletting after mixing in mixing machine, hardness control between 130N~160N, and tablet weight variation is controlled ± 3%.
Prescription 16-weigh microcrystalline cellulose, hydroxypropylcellulose EXF, crospovidone, magnesium stearate, silica and Ah
Si Patan is premixed, the tabletting after mixing in mixing machine with pulse 1, pulse 2, pulse 3 afterwards, hardness control 130N~
Between 160N, tablet weight variation is controlled ± 3%.
3% (w/w) is 1. added in the homogeneous mixture of the microcrystalline cellulose into wet granulator and lactose for prescription 17-
PVP K30 aqueous solution pelletize, after 50 DEG C of dryings cross 24 mesh sieve it is spare；2. weighing pulse 1, pulse 2, pulse 3, dilution
The tabletting after mixing in mixing machine of agent particle, crospovidone, magnesium stearate, silica, hardness control 130N~
Between 160N, tablet weight variation is controlled ± 3%.
Prescription 18-1. weighs microcrystalline cellulose, lactose, hydroxypropylcellulose EXF and is made in dry granulating machine after mixing
Grain, sieve grain size are 0.5mm；2. weighing pulse 1, pulse 2, pulse 3, diluent particle, Sucralose, crospovidone, hard
The tabletting after mixing in mixing machine of fatty acid magnesium, silica, hardness control between 130N~160N, and tablet weight variation control exists
± 3%.
The dissolution characteristic of 9 sample of embodiment in water
Dissolving-out method：Slurry processes, rotating speed 100rpm, the medium temperature of 2015 editions four 0,931 second law regulations of Chinese Pharmacopoeia
It it is 37 DEG C ± 0.5 DEG C, dissolution medium is 900ml water, and 0.45 μm of filter is crossed respectively at sample dissolution 0.25h, 0.5h, 1h sampling 5ml
Film measures the Amoxicillin in dissolution fluid according to the lower content assaying method sample introduction in Chinese Pharmacopoeia 2015 editions two Amoxicillins
Content, calculate the preparation of Amoxicillin.
It is as shown in the table according to the preparation of the made sample of embodiment in water：
Test result shows that comparison coats pulse 1 (prescription 5,6), pulse 2 (prescription 9,10) and the pulse 3 of clothing layer soluble in the stomach
(prescription 13,14), uncoated clothing layer soluble in the stomach only coat the Amoxicillin ball (prescription 3,4) of separation layer, and uncoated clothing layer soluble in the stomach is only
The Amoxicillin ball (prescription 7,8) and uncoated clothing layer soluble in the stomach for coating Eudragit enteric coating layers only coat AQOAT enteric coating layers
Amoxicillin ball (prescription 11,12) occur the dissolution of apparent drug leakage phenomenon-prescription 3,4 when dissolving out 15 minutes and exist
90% or more, 85% or more, prescription 11,12 is dissolved out 60% or more the dissolution of prescription 9,10.Test result prompts, and piece is in water
During dispersion, the drug in each impulse pellet of uncoated clothing layer soluble in the stomach has to be revealed to some extent, and the time is longer, lets out
Leakage quantity is higher, to make each impulse pellet not controlled and be caused the release in advance of dosage by pH in digestive tract after entering in vivo, loses
Go the treatment advantage of pulse release, it is also possible to so that patient is generated serious adverse reaction because dosage comes down in torrents.
Embodiment 10 prepares amoxicillin tablets (the single dose composition such as following table containing pulse 1 ', pulse 2 ' and pulse 3 '
It is shown, unit：Mg prepares batch：2000)
Preparation method：Prescription 19-weighs pulse 1 ', pulse 2 ', pulse 3 ', microcrystalline cellulose, crospovidone, tristearin
The tabletting after mixing in mixing machine of sour magnesium, silica, hardness control between 130N~160N, tablet weight variation control ±
3%.
Prescription 20-weigh microcrystalline cellulose, hydroxypropylcellulose EXF, crospovidone, magnesium stearate, silica and Ah
Si Patan is premixed, the tabletting after mixing in mixing machine with pulse 1 ', pulse 2 ', pulse 3 ' afterwards, and hardness control exists
Between 130N~160N, tablet weight variation is controlled ± 3%.
3% (w/w) is 1. added in the homogeneous mixture of the microcrystalline cellulose into wet granulator and lactose for prescription 21-
PVP K30 aqueous solution pelletize, after 50 DEG C of dryings cross 24 mesh sieve it is spare；2. weigh pulse 1 ', pulse 2 ', pulse 3 ',
The tabletting after mixing in mixing machine of diluent particle, crospovidone, magnesium stearate, silica, hardness control exist
Between 130N~160N, tablet weight variation is controlled ± 3%.
Prescription 22-1. weighs microcrystalline cellulose, lactose, hydroxypropylcellulose EXF and is made in dry granulating machine after mixing
Grain, sieve grain size are 0.5mm；2. weigh pulse 1 ', pulse 2 ', pulse 3 ', diluent particle, Sucralose, crospovidone,
The tabletting after mixing in mixing machine of magnesium stearate, silica, hardness control between 130N~160N, tablet weight variation control
± 3%.
The mouthfeel of 10 comparative example 8 of embodiment and 10 sample of embodiment
Method：8-prescription of Example 15~18 and 10-prescription of embodiment, 19~22 gained sample strip are appropriate, and every molten
In about 100ml water, after shaking 3 minutes, the liquid sample that number is 1~8 allows 10 volunteers to taste liquid mouthfeels, root at random
Give a mark to every part of sample liquid according to following mouth feel score standard, after take average score value as sensory test result.
As a result：
| Prescription serial number | Score (mean scores) |
| 15 | 2.0 |
| 16 | 4.8 |
| 17 | 2.0 |
| 18 | 4.5 |
| 19 | 1.1 |
| 20 | 3.4 |
| 21 | 1.5 |
| 22 | 3.2 |
The results show that have clear improvement in mouthfeel of the prescription 15~18 compared with 19~20 gained sample liquid of prescription, the reason is that
Since 19~20 gained liquid sample of prescription has drug-eluting to cause mouthfeel partially bitter, and depositing because of clothing layer soluble in the stomach in prescription 15~18
It is revealed substantially without drug after making piece disperse in water, therefore liquid bitter taste the unobvious, (place when sweetener is added in prescription
Square 16,18), sweet taste is more prominent.
The dissolution characteristic of 11 comparative example 8 of embodiment and 10 sample of embodiment
This experimental simulation patient takes the process of amoxicillin tablets, is first placed in piece and fills 37 DEG C ± 0.5 DEG C of 100ml water
Beaker in, shaking pours into 900ml stripping rotors after 3 minutes, and the phosphate buffer that 800ml pH4.0 are added (takes partial buffer
Merge final 900ml dissolution mediums after liquid cleaning beaker, if it is necessary, adjustment dissolution medium pH value is to 4.0 ± 0.05 ranges
It is interior).
Dissolving-out method：Slurry processes, rotating speed 100rpm, the medium temperature of 2015 editions four 0,931 second law regulations of Chinese Pharmacopoeia
It is 37 DEG C ± 0.5 DEG C, medium volume total 900ml, 0h~2h：PH4.0 phosphate buffers；2h~4h adds appropriate NaOH solution
Phosphate buffer pH value is adjusted to 6.0；4h~6h adds appropriate NaOH solution to adjust phosphate buffer pH value to 6.8, respectively
0.45 μm of filter is crossed in sample dissolution 0.25h, 0.5h, 1h, 2h, 2.25h, 2.5h, 3h, 4h, 4.25h, 4.5h, 5h, 6h sampling 5ml
Film measures the Amoxicillin in dissolution fluid according to the lower content assaying method sample introduction in Chinese Pharmacopoeia 2015 editions two Amoxicillins
Content, calculate the preparation of Amoxicillin.
As a result：
Test result shows that the dissolution of 8 sample of comparative example (prescription 15~18) is as a result, the sample of embodiment 10 (is located
Side 19~22) have no the protection of clothing layer soluble in the stomach because of the pulse 1 ', pulse 2 ', pulse 3 ' of composition, therefore when disperseing in water, pulse 2 '
And the enteric coating layer of pulse 3 ' has the release in advance that different degrees of dissolving leads to drug, also because in piece dispersion process in water
Film clothing dissolution degree is not in regularity, therefore the asking there is also each stage pulse homogeneity difference of the dissolution data between prescription 19~22
Topic.By the data of prescription 19~22 it is found that sample in 3 kinds of pH value stages each 2 hours release characteristics not at pulsed release
Feature, with commercially available medicineRelease mode have notable difference, refer to Figure of description 1.
By Figure of description 2 it is found that prescription 15~18 and commercially available medicineStripping curve it is close, pass through phase
Like factor f2Known to result of calculation (shown in following table), the similar factors f of prescription 15~18 and commercially available medicine250 are all higher than, dissolution characteristic
WithIt is similar.
| Prescription serial number | 15 | 16 | 17 | 18 |
| Similar factors f2 | 81.5 | 91.4 | 89.0 | 84.6 |
12 comparative example of embodiment, 8 made sample and commercially available medicineRelated substance and Amoxicillin it is poly-
Close object
Assay method：Sample is carried out according to method under related substance item in 2015 editions two Amoxicillin monographs of Chinese Pharmacopoeia
And commercially available medicineRelated substance-measuring, Amoxicillin polymerize method below items carry out sample and commercially available medicine Ah
Amdinocillin polymer measures, and the results are shown in table below.
The results show that the related substance and Amoxicillin polymer result of own product are superior to commercially available medicine
13 embodiment of embodiment, 8 made sample and commercially available medicineAccelerated stability test
By 15~prescription of prescription, 18 made sample and commercially available medicine(use identical high-density polyethylene bottle packet
Dress, 30 every bottle) it is placed 6 months under the conditions of 40 DEG C ± 2 DEG C, RH75% ± 5%, take appropriate sample in 0 day, 3 months, 6 months
Product carry out index of correlation (content, dissolution rate, related substance and Amoxicillin polymer) detection.
Assay method：The content of sample is according to assay item lower section in 2015 editions two Amoxicillin monographs of Chinese Pharmacopoeia
Method carries out, the related substance of sample according to method under related substance item in 2015 editions two Amoxicillin monographs of Chinese Pharmacopoeia into
Row, the polymer of sample according in 2015 editions two Amoxicillin monographs of Chinese Pharmacopoeia below Amoxicillin polymerization items method into
Row, the results are shown in table below.
The results show that 15~18 gained sample of prescription is each after being placed 6 months under accelerated test condition (40 DEG C, RH75%)
The testing result of item index is better than commercially available medicineAnd the variation degree for comparing 0 day indices testing result is small
In commercially available medicineIllustrate that the stability for making sample by oneself is better than the commercially available medicine of film coating
The related substance inspection after being placed 6 months under accelerated test condition (40 DEG C, RH75%) of 15~18 gained sample of prescription
It surveys result and is substantially better than 19 gained sample of prescription, the variation degree that 0 day testing result is compared in relation to substance testing result is less than place
19 gained samples of side illustrate the stability for making sample by oneself better than pulse 1 ', pulse 2 ' and the arteries and veins directly by uncoated clothing layer soluble in the stomach
Rush the self-control sample 19 obtained by 3 ' tablettings.
Claims (9)
1. a kind of improved amoxicillin tablets, it is characterised in that the piece be by 1 pellet of pulse, 2 pellet of pulse, 3 pellet of pulse with
Tabletting is made pharmaceutically acceptable excipient after mixing；Active constituent dosage in 1 pellet of pulse accounts for active in every
The 45% of ingredient accumulated dose, the active constituent dosage in 2 pellet of pulse account for the 30% of every middle active constituent accumulated dose, pulse 3
Active constituent dosage in pellet accounts for the 25% of every middle active constituent accumulated dose；1 pellet of pulse is not from inside to outside successively by Ah
XiLin capsule core, separation layer and coatings soluble in the stomach are constituted；2 pellet of pulse is from inside to outside successively by Amoxicillin capsule core, enteric coating
Layer and coatings soluble in the stomach are constituted；3 pellet of pulse is from inside to outside successively by Amoxicillin capsule core, enteric coat layer and coatings soluble in the stomach
It constitutes, the filmogen of the coatings soluble in the stomach in 3 pellet of pulse 1, pulse 2 and pulse is selected from methyl methacrylate and diethyl
Aminoethyl methacrylate 7:30% aqueous dispersion of 3 copolymer, the filmogen of the enteric coat layer in 2 pellet of pulse
Selected from methacrylic acid and ethyl acrylate 1:1 copolymer or its 30% aqueous dispersion, the enteric coat layer in 3 pellet of pulse
Filmogen be selected from hydroxypropyl methylcellulose acetate succinate AS-HF types.
2. a kind of improved amoxicillin tablets according to claim 1, it is characterised in that the composition of 1 pellet of pulse is such as
Under：
(1) Amoxicillin capsule core：The percentage that each ingredient accounts for Amoxicillin capsule core gross weight is as follows：
(2) separation layer：The percentage that each ingredient accounts for separation layer gross weight is as follows：
Filmogen 80%~95%
Plasticizer 5%~20%
Separation layer directly selects stomach dissolution typeFilm coating pre-mix dose, weightening：Separation layer weightening is Amoxicillin capsule core
The 4%~8% of gross weight；
(3) coatings soluble in the stomach：The percentage that each ingredient accounts for coatings gross weight soluble in the stomach is as follows：
Methyl methacrylate and diethyl amino ethyl group methacrylate 7:30% aqueous dispersion of 3 copolymer, with polymer
Dry weight meter 60%~70%
Weightening：Coatings weightening soluble in the stomach is 4%~8% of the Amoxicillin capsule core gross weight comprising separation layer；
Wherein, the diluent in Amoxicillin capsule core composition is selected from microcrystalline cellulose or powdered cellulose, and adhesive is selected from hydroxypropyl
Methylcellulose or hydroxypropylcellulose, wetting agent are selected from Emulsifier EL-35 or lauryl sodium sulfate；In separation layer composition
Filmogen is selected from hydroxypropyl methylcellulose or hydroxypropylcellulose or hydroxyethyl cellulose, and plasticizer is selected from glycerine, propylene glycol, poly- second
It is any in glycol, triethyl citrate, triacetin, triacetyl glycerine, monoacetin；Coatings composition soluble in the stomach
In, plasticizer is selected from triethyl citrate, tributyl citrate, acetyl triethyl citrate/docusate sodium, acetyl tributyl citrate three
Any in butyl ester/docusate sodium, dibutyl sebacate/docusate sodium, antiplastering aid is selected from talcum powder, and antioxidant is selected from dibutyl hydroxyl
Base toluene, colorant are appointed in water colo(u)r, fat-soluble pigment, water-insoluble aluminum lake, titanium dioxide, iron oxides
One.
3. a kind of improved amoxicillin tablets according to claim 1, it is characterised in that 2 pellet of pulse is from inside to outside successively
It is made of Amoxicillin capsule core, enteric coat layer and coatings soluble in the stomach, wherein the prescription of Amoxicillin capsule core and coatings soluble in the stomach
Composition is as follows：
Amoxicillin capsule core：The percentage that each ingredient accounts for Amoxicillin capsule core gross weight is as follows：
Coatings soluble in the stomach：The percentage that each ingredient accounts for coatings gross weight soluble in the stomach is as follows：
Methyl methacrylate and diethyl amino ethyl group methacrylate 7:30% aqueous dispersion of 3 copolymer, with polymer
Dry weight meter 60%~70%
Coatings weightening soluble in the stomach is 4%~8% of the Amoxicillin capsule core gross weight comprising enteric coat layer, and in enteric coat layer
The percentage that each ingredient accounts for enteric coat layer gross weight is as follows：
Methacrylic acid and ethyl acrylate 1:1 copolymer or its 30% aqueous dispersion, 50% in terms of polymer dry weight~
70%
Plasticizer 10%~25%
Antiplastering aid 15%~30%
Plasticizer is selected from polyethylene glycol, acetyl triethyl citrate, citric acid in the enteric coat layer composition of 2 pellet of above-mentioned pulse
Any in triethyl, antiplastering aid is selected from talcum powder, and enteric coat layer weightening is the 15%~20% of Amoxicillin capsule core gross weight.
4. a kind of improved amoxicillin tablets according to claim 1, it is characterised in that 3 pellet of pulse is from inside to outside successively
It is made of Amoxicillin capsule core, enteric coat layer and coatings soluble in the stomach, wherein the prescription of Amoxicillin capsule core and coatings soluble in the stomach
Composition is as follows：
Amoxicillin capsule core：The percentage that each ingredient accounts for Amoxicillin capsule core gross weight is as follows：
Coatings soluble in the stomach：The percentage that each ingredient accounts for coatings gross weight soluble in the stomach is as follows：
Methyl methacrylate and diethyl amino ethyl group methacrylate 7:30% aqueous dispersion of 3 copolymer, with polymer
Dry weight meter 60%~70%
Coatings weightening soluble in the stomach is 4%~8% of the Amoxicillin capsule core gross weight comprising enteric coat layer, and in enteric coat layer
The percentage that each ingredient accounts for enteric coat layer gross weight is as follows：
Weightening：Enteric coat layer weightening is the 20%~25% of Amoxicillin capsule core gross weight.
5. a kind of improved amoxicillin tablets according to claim 1, it is characterised in that the pharmaceutically acceptable tax
Shape agent is selected from the combination of one or more of diluent, adhesive, disintegrant, lubricant, glidant, corrigent, the figuration
Agent can be presented by the particle form of wet granulation, dry granulation, or individually or in the form of powder mixes be presented by powder；Its
In, diluent is any in starch, microcrystalline cellulose, pregelatinized starch, calcium monohydrogen phosphate, lactose, sucrose, sugar alcohol；Adhesive
It is any in hydroxypropyl methylcellulose, hydroxypropylcellulose, hydroxyethyl cellulose, polyvinylpyrrolidone, sodium carboxymethylcellulose；
Disintegrant is any in starch, pregelatinized starch, carboxyrnethyl starch sodium, hydroxypropul starch or microcrystalline cellulose, flour
Any or crospovidone in element, croscarmellose sodium, calcium carboxymethylcellulose；Lubricant be selected from magnesium stearate or
Sodium stearyl fumarate；Glidant is selected from silica；Corrigent is any in aspartame, acesulfame potassium, Sucralose.
6. a kind of improved amoxicillin tablets according to claim 1, it is characterised in that the preparation process of 1 pellet of pulse is such as
Under：
(1) prepared by Amoxicillin capsule core
It is dissolved in the water adhesive and wetting agent to form binder solution, by size controlling in 100 mesh Amoxicillin below
It is placed in wet granulator and is uniformly mixed with diluent, binder solution softwood is added in mixed process, be made above-mentioned
Softwood is placed in extruder and is squeezed out, and collection extrusion item, which is placed in spheronizator, carries out round as a ball pelletization operation, and 40 DEG C~45 DEG C dry
Capsule core of the collection cut size between the mesh of 30 mesh~60, spare after dry；
(2) packet separation layer
By filmogen and plasticizer or directly by stomach dissolution typeFilm coating pre-mix dose is configured to be coated with suitable quantity of water
Amoxicillin capsule core is placed in fluid bed and is coated by liquid, and separation layer weightening is the 4%~8% of Amoxicillin capsule core gross weight；
(3) clothing layer soluble in the stomach is wrapped
By methyl methacrylate and diethyl amino ethyl group methacrylate 7:30% aqueous dispersion of 3 copolymer, antiplastering aid,
Antioxidant, plasticizer, colorant are dispersed in water to form Coating Solution, and the Amoxicillin pellet for being surrounded by separation layer is placed in fluidisation
Be coated in bed, clothing layer soluble in the stomach weightening accounts for the 4%~8% of the pellet gross weight of Amoxicillin containing separation layer, after will coating gained pellet in
Dry at 40 DEG C~45 DEG C, 40 DEG C~50 DEG C cure at least 24 hours.
7. a kind of improved amoxicillin tablets according to claim 1, it is characterised in that the preparation process of 2 pellet of pulse is such as
Under：
(1) prepared by Amoxicillin capsule core
It is dissolved in the water adhesive and wetting agent to form binder solution, by size controlling in 100 mesh Amoxicillin below
It is placed in wet granulator and is uniformly mixed with diluent, binder solution softwood is added in mixed process, be made above-mentioned
Softwood is placed in extruder and is squeezed out, and collection extrusion item, which is placed in spheronizator, carries out round as a ball pelletization operation, and 40 DEG C~45 DEG C dry
Capsule core of the collection cut size between the mesh of 30 mesh~60, spare after dry；
(2) enteric-coating layer
By methacrylic acid and ethyl acrylate 1:1 copolymer or its 30% aqueous dispersion, plasticizer, antiplastering aid suitable quantity of water
It is configured to coating solution, Amoxicillin capsule core is placed in fluid bed and is coated, enteric coating layer weightening is Amoxicillin capsule core gross weight
15%~20%, after coating micro-pill is dry at 40 DEG C~45 DEG C, 40 DEG C~50 DEG C cure at least 24 hours；
(2) clothing layer soluble in the stomach is wrapped
By methyl methacrylate and diethyl amino ethyl group methacrylate 7:30% aqueous dispersion of 3 copolymer, antiplastering aid,
Antioxidant, plasticizer, colorant are dispersed in water to form Coating Solution, and the Amoxicillin pellet for being surrounded by enteric coating layer is placed in stream
Change and be coated in bed, clothing layer soluble in the stomach weightening accounts for the 4%~8% of the pellet gross weight of Amoxicillin containing enteric coating layer, after will coating gained it is micro-
Ball is dry at 40 DEG C~45 DEG C, and 40 DEG C~50 DEG C cure at least 24 hours.
8. a kind of improved amoxicillin tablets according to claim 1, it is characterised in that the preparation process of 3 pellet of pulse is such as
Under：
(1) prepared by Amoxicillin capsule core
It is dissolved in the water adhesive and wetting agent to form binder solution, by size controlling in 100 mesh Amoxicillin below
It is placed in wet granulator and is uniformly mixed with diluent, binder solution softwood is added in mixed process, be made above-mentioned
Softwood is placed in extruder and is squeezed out, and collection extrusion item, which is placed in spheronizator, carries out round as a ball pelletization operation, and 40 DEG C~45 DEG C dry
Capsule core of the collection cut size between the mesh of 30 mesh~60, spare after dry；
(2) enteric-coating layer
Hydroxypropyl methylcellulose acetate succinate AS-HF types, triethyl citrate, talcum powder, lauryl sodium sulfate are used suitable
Amount water is configured to coating solution, and Amoxicillin capsule core is placed in fluid bed and is coated, and enteric coating layer weightening is that Amoxicillin capsule core is total
The 20%~25% of weight；
(3) clothing layer soluble in the stomach is wrapped
By methyl methacrylate and diethyl amino ethyl group methacrylate 7:30% aqueous dispersion of 3 copolymer, antiplastering aid,
Antioxidant, plasticizer, colorant are dispersed in water to form Coating Solution, and the Amoxicillin pellet for being surrounded by enteric coating layer is placed in stream
Change and be coated in bed, clothing layer soluble in the stomach weightening accounts for the 4%~8% of the pellet gross weight of Amoxicillin containing enteric coating layer, after will coating gained it is micro-
Ball is dry at 40 DEG C~45 DEG C, and 40 DEG C~50 DEG C cure at least 24 hours.
9. a kind of improved amoxicillin tablets according to claim 1, it is characterised in that the piece is in Chinese Pharmacopoeia 2015 editions
Slurry processes, rotating speed 100rpm, dissolution medium 900ml, the medium temperature of four 0,931 second law regulations be 37 DEG C ± 0.5 DEG C,
PH value is respectively that the dissolution characteristic in 4.0,6.0 and 6.8 phosphate buffer is as follows：
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|---|---|---|---|---|
| CN102397262A (en) * | 2010-09-15 | 2012-04-04 | 重庆医药工业研究院有限责任公司 | Amoxicillin sustained release solid medicinal composition and preparation method thereof |
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| CN102397262A (en) * | 2010-09-15 | 2012-04-04 | 重庆医药工业研究院有限责任公司 | Amoxicillin sustained release solid medicinal composition and preparation method thereof |
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| Title |
|---|
| pH依赖型阿莫西林多重脉冲微丸的制备;王爱明，等;《医药导报》;20130331;第32卷(第3期);第387-391页 * |
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