CN105832691B - A kind of degree draws glycopeptide site specific DDS for colon sustained release preparation and preparation method thereof - Google Patents
A kind of degree draws glycopeptide site specific DDS for colon sustained release preparation and preparation method thereof Download PDFInfo
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- CN105832691B CN105832691B CN201610375814.2A CN201610375814A CN105832691B CN 105832691 B CN105832691 B CN 105832691B CN 201610375814 A CN201610375814 A CN 201610375814A CN 105832691 B CN105832691 B CN 105832691B
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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
- A61K9/2886—Dragees; Coated pills or tablets, e.g. with film or compression coating having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/02—Peptides of undefined number of amino acids; 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
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
-
- 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
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
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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
Abstract
The present invention relates to polypeptide drugs positioning and slow release formulation arts more particularly to a kind of degree to draw glycopeptide site specific DDS for colon sustained release preparation and preparation method thereof.The site specific DDS for colon sustained release preparation is made of label or capsule core, slow release layer, pH control layers, flora trigger layer.The site specific DDS for colon sustained release preparation can realize that the purpose of positioning and slow release drug, degree of improving draw the bioavilability of glycopeptide, reduce toxic side effect, compared with injection, especially alleviate the stimulation to gastrointestinal tract, improve patient's compliance.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, and in particular to a kind of degree draws glycopeptide site specific DDS for colon sustained release preparation and its preparation side
Method.
Background technology
It is a kind of -1 receptor stimulating agent of novel glp-1 that degree, which draws glycopeptide (dulaglutide, LY2189265), by Lilly public affairs
Department's exploitation, the end of the year 2014 obtain FDA approval listings.Degree draws glycopeptide to be combined activation born of the same parents by the GLP-1 receptors with cell membrane surface
Interior Signal Transduction access adjusts cell function, promotes insulin synthesis and secretion, hence it is evident that reduce the blood glucose of diabetic
With glycosylated hemoglobin (HbA1c).
Degree draws the effect of glycopeptide control blood glucose to be better than current most popular oral hypoglycemic agents melbine, and helps
In the weight for mitigating patient；The research of multinomial relevant clinical shows that it is that a kind of higher super long effective of safety and efficacy is controlled
Treat diabetes B drug；Be also only one in III phase clinic therapeutic equivalence in the GLP-1 receptor agonisms of liraglutide
Agent, industry predict that the annual sales amount of its year two thousand twenty is up to 1,300,000,000 dollars.
The administering mode that degree draws glycopeptide current is to be subcutaneously injected once weekly, is also deposited although having a good application prospect
In some shortcomings：Slow down gastric emptying, causes gastroparesis；Nausea, diarrhea, vomiting, abdominal pain etc. are its most common adverse reactions；It is long
Phase drug administration by injection, injection site have the stimulations such as pain, scleroma, fash or erythema, cause suffering to patient, patient compliance
Difference.For this purpose, providing a kind of administering mode smaller to GI irritation, compliance is good, the clinical application of glycopeptide is drawn to have degree
There is realistic meaning.
Oral colon-specific drug delivery system is a kind of novel medicine-releasing system to grow up in recent years, which uses
One or more preparation techniques make drug by oral administration after do not discharge drug in stomach and small intestine, reach colon and discharge drug, make
Drug plays locally or systemically therapeutic effect.By digestive ferment, sour water solution, cross-film absorption difference after being administered orally due to polypeptide drug
With the influence of first pass effect, application of such drug in terms of oral administration is limited.And oral colon positioning feed system
System shows the advantage in oral medication, which can avoid polypeptide drug from being destroyed by stomach, intestines enzyme, to improve
Its bioavilability compensates for the deficiency for the polypeptide drug for needing frequent drug administration by injection, is provided very well for oral polypeptide drugs
Approach.
The proteolysis enzyme concentration of colon site is much smaller than other sections of alimentary canal, and drug is in the position residence time
Longer (up to 8 hours or more), the resistance that colon wall penetrates macromolecular is also smaller than intestinal wall, is conducive to drug and fully absorbs, will
Sustained release preparation is made in drug, more extends the release time of drug, reduces administration number of times, patient is facilitated to apply.
Invention content
Deficiency in view of the above technology, a kind of degree of present invention offer draw glycopeptide site specific DDS for colon sustained release preparation and its preparation side
Method, the site specific DDS for colon sustained release preparation can realize the purpose of positioning and slow release drug, be capable of the bioavilability of degree of raising drawing glycopeptide,
Its toxic side effect is reduced, compared with injection, the stimulation to gastrointestinal tract is especially alleviated, improves patient's compliance.
In order to achieve the above-mentioned object of the invention, the present invention provides following technical scheme：
Specifically, the present invention provides a kind of degree to draw glycopeptide site specific DDS for colon sustained release preparation, by label or capsule core, sustained release
Layer, pH control layers, flora trigger layer composition.
By weight, drug containing label or capsule core account for 30~60%, slow release layer account for 15~30%, pH control layers account for 10~
30%, flora trigger layer accounts for 15~40%.
Label or capsule core include that main ingredient degree draws glycopeptide, diluent, binder and disintegrant；The slow release layer includes sustained release material
Material, plasticizer and pore-foaming agent；The pH control layers include enteric material, antiplastering aid and plasticizer；The flora trigger layer includes
Flora triggers material, bleeding agent, antiplastering aid and plasticizer.
Label or capsule core by 10~50% main ingredient degree draw glycopeptide, 5~20% diluent, 10~30% binder and
15~40% disintegrants form.
In label or capsule core, diluent is one or more in starch, microcrystalline cellulose, mannitol, dextrin.
Preferably, diluent is selected from starch, mannitol.
In label or capsule core, binder is selected from polyvinylpyrrolidone (PVP), polyethylene glycol, starch slurry, carboxymethyl cellulose
It is one or more in element, hydroxypropyl methyl cellulose.
Preferably, binder is selected from polyvinylpyrrolidone (PVP), carboxymethyl cellulose, hydroxypropyl methyl cellulose
It is one or more.
In label or capsule core, disintegrant is selected from crosslinked polyvinylpyrrolidone, sodium carboxymethyl starch, starch, microcrystalline cellulose
It is one or more in element, low-substituted hydroxypropyl cellulose.
Preferably, disintegrant is selected from crosslinked polyvinylpyrrolidone, microcrystalline cellulose, low-substituted hydroxypropyl cellulose.
Slow release layer is made of 40~80% slow-release material, 5~35% the plasticizers and 5~35% pore-foaming agent.
In slow release layer, slow-release material is selected from ethyl cellulose, sodium alginate, tragacanth, methylcellulose, hydroxyl second fiber
Element, hydroxypropyl second cellulose, sodium carboxymethylcellulose, chitin, galactomannan, polyvinyl alcohol, gathers hydroxypropyl methylcellulose
It is one or more in carboxylic ethylene.
Preferably, slow-release material is one or more in ethyl cellulose, hyetellose, polyvinyl alcohol.
In slow release layer, plasticizer can be selected from one or more in polyethylene glycol, tartaric acid, citric acid.
In slow release layer, pore-foaming agent can be selected from selected from starch, xylose, potassium chloride, sodium chloride, dibastic sodium phosphate, potassium hydrogen phosphate, phosphorus
It is one or more in acid dihydride sodium, disodium hydrogen phosphate.
PH control layers are made of 30~80% enteric material, 8~30% antiplastering aid and 8~30% plasticizer.
In pH control layers, enteric material be selected from Eudragit L100, Eudragit S100, Eudragit FS,
It is one or more in Eudragit E, acrylic resin II, acrylic resin III.
In pH control layers, antitackiness agent is one or more in talcum powder, magnesium stearate, glycerin monostearate.
In pH control layers, plasticizer be selected from diethyl phthalate, dibutyl phthalate, triethyl citrate,
It is one or more in glyceryl triacetate, methyl hydroxybenzoate.
Preferably, plasticizer is one or more in triethyl citrate, glyceryl triacetate, methyl hydroxybenzoate.
Flora trigger layer is by 40~75% flora triggering material, 5~25% bleeding agents, 5~15% described anti-stick
Agent and 5~20% plasticizer composition.
In flora trigger layer, flora triggers the one kind or more of material in chitosan, alginate, pectin, guar gum
Kind.
In flora trigger layer, bleeding agent be selected from Eudragit RL30D, EudragitRS30D, Eudragit NE or
It is one or more in Eudragit NM；
Preferably, bleeding agent is selected from EudragitRL30D, EudragitRS30D.
In flora trigger layer, the one kind or more of antitackiness agent in medicinal talcum powder, magnesium stearate, glycerin monostearate
Kind.
In flora trigger layer, plasticizer is selected from diethyl phthalate, dibutyl phthalate, lemon triethylenetetraminehexaacetic acid
It is one or more in ester, glyceryl triacetate, methyl hydroxybenzoate.
Preferably, plasticizer is one or more in triethyl citrate, glyceryl triacetate and methyl hydroxybenzoate.
The present invention also provides the preparation methods that a kind of degree draws glycopeptide site specific DDS for colon sustained release preparation, include the following steps：
1) prepared by label or capsule core
It is prepared by label：It draws glycopeptide, diluent and disintegrant to be uniformly mixed main ingredient degree, adhesive is added, softwood, mistake is made
Sieve granulation, drying, whole grain of being sieved, tabletting keep hardness in 50.0 ± 6.3N/cm when tabletting2In range；
It is prepared by capsule core：Using blank capsule core as carrier, solution or suspension is made in drug, makes drug in a fluidized bed
Solution spraying is wrapped in blank capsule core, is prepared and is carried pill core；
2) slow release layer is coated：With slow release layer Coating Solution by drug containing label obtained in 1) or capsule core in rolling seed-coating machine
It is sprayed to label or capsule core surface using side spray mode, it is 3~5 hours dry in 45~60 DEG C of electric drying oven with forced convections；
3) pH control layers are coated：Sustained release label obtained in 2) or capsule core are passed through into spraying-with pH control layers Coating Solution
Turnadle pan coating or fluidized bed coating are coated, and are sprayed with drying alternately, 0.5~5kg/cm of atomizing pressure2, air inlet
45~60 DEG C of temperature, 1.5~3mL/min of hydrojet speed；
4) flora trigger layer is prepared：PH control layers label obtained in 3) or capsule core are passed through into spray with flora trigger layer solution
Mist-turnadle pan coating or fluidized bed coating are coated, and are sprayed with drying alternately, 0.5~5kg/cm of atomizing pressure2,
45~60 DEG C of inlet air temperature, 1.5~3mL/min of hydrojet speed；
Description of the drawings
Fig. 1 shows In-vitro release curves in embodiment 11.
Specific implementation mode
Embodiment of the present invention is described in detail below in conjunction with embodiment, but those skilled in the art will manage
Solution, the following example is merely to illustrate the present invention, and should not be taken as limiting the scope of the invention.
The preparation of 1 degree of drawing glycopeptide colon-targeted sustained-release tablets agent of embodiment
Core formulation：
Slow release layer prescription：
PH control layer prescriptions：
II 37.5g of acrylic resin
Talcum powder 12.5g
Triethyl citrate 12.5g
Flora trigger layer prescription：
Preparation process：
Drug containing label：Degree draws glycopeptide, mannitol, microcrystalline cellulose to be uniformly mixed using the method for equal increments, crosses 100 mesh
Softwood is made in the polyvinylpyrrolidonesolution solution of sieve, addition absolute ethyl alcohol dissolving, crosses 24 mesh and sieves, granulation, is done for 60 DEG C in fluid bed
Dry 1.5h crosses 40 mesh sieves, tabletting；
Slow release layer is coated：Ethyl cellulose, sodium alginate, polyethylene glycol and xylose are dissolved in absolute ethyl alcohol and are configured to
10% coating solution is sprayed using side spray mode to piece wicking surface in rolling seed-coating machine, is done in 45 DEG C of electric drying oven with forced convections
Dry 3 hours；
PH control layers are coated：Acrylic resin II, talcum powder and triethyl citrate are dissolved in absolute ethyl alcohol and are configured to
25% coating solution takes intermittent spray operation in rolling seed-coating machine, and alternately with drying, atomizing pressure is for spraying
3.0kg/cm2, 50 DEG C of inlet air temperature, hydrojet speed 1.5mL/min needs to continuously stir coating solution in coating process.
Flora trigger layer is coated：Pectin, EudragitRL30D, medicinal talcum powder and glyceryl triacetate are dissolved in anhydrous
18% coating solution is configured in ethyl alcohol, coating method is identical as pH control layer coating operations.
Degree is made and draws glycopeptide colon-targeted sustained-release tablets agent 1000.
2 degree of embodiment draws the preparation of glycopeptide site specific DDS for colon sustained release pill
Capsule core prescription：
Slow release layer prescription：
Ethyl cellulose 22.5g
Tartaric acid 9.4g
Potassium hydrogen phosphate 5.6g
PH control layer prescriptions：
EudragitL100 35.0g
Magnesium stearate 9.0g
Methyl hydroxybenzoate 6.0g
Flora trigger layer prescription：
Preparation process：
It draws glycopeptide, starch, polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose to be dissolved in absolute ethyl alcohol degree to mix
Even, the blank capsule core 500g for weighing 45 mesh is placed in fluid bed, and drug solution spraying is wrapped in blank capsule core, prepares and carries medicine
Capsule core；
Slow release layer is coated：Ethyl cellulose, tartaric acid and potassium hydrogen phosphate are dissolved in be configured in absolute ethyl alcohol 15% packet
Clothing liquid is placed in rolling seed-coating machine and is coated, 5 hours dry in 40 DEG C of electric drying oven with forced convections；
PH control layers are coated：EudragitL100, magnesium stearate and methyl hydroxybenzoate are dissolved in absolute ethyl alcohol and are configured to
30% coating solution takes intermittent spray operation in rolling seed-coating machine, and alternately with drying, atomizing pressure is for spraying
4.5kg/cm2, 55 DEG C of inlet air temperature, hydrojet speed 2.0mL/min needs to continuously stir coating solution in coating process.
Flora trigger layer is coated：Pectin, EudragitRL30D, medicinal talcum powder and glyceryl triacetate are dissolved in anhydrous
18% coating solution is configured in ethyl alcohol, coating method is identical as PH control layer coating operations.
Flora trigger layer is coated：Chitosan, EudragitRS30D, glycerin monostearate and lemon triethylenetetraminehexaacetic acid ester are dissolved in
15% coating solution is configured in absolute ethyl alcohol, coating method is identical as PH control layer coating operations.
The preparation of 3 degree of drawing glycopeptide site specific DDS for colon spansule of embodiment
Capsule core prescription：
Slow release layer prescription：
Hydroxypropyl methylcellulose 20.0g
Citric acid 17.5g
Disodium hydrogen phosphate 12.5g
PH control layer prescriptions：
Eudragit S100 32.0g
Magnesium stearate 4.0g
Glyceryl triacetate 4.0g
Flora trigger layer prescription：
Preparation process：
Pellet core：Glycopeptide, starch, carboxymethyl cellulose and cross-linked pvp is drawn to be dissolved in 85% ethyl alcohol degree molten
It is uniformly mixed in liquid, the blank capsule core 500g for weighing 60 mesh is placed in fluid bed, and drug solution spraying is wrapped in blank capsule core
On, it prepares and carries pill core；
Slow release layer is coated：Hydroxypropyl methylcellulose, citric acid, disodium hydrogen phosphate are dissolved in absolute ethyl alcohol and are configured to 20%
Coating solution is sprayed using side spray mode to piece wicking surface in rolling seed-coating machine, and dry 3 is small in 40 DEG C of electric drying oven with forced convections
When；
PH control layers are coated：Eudragit S100, magnesium stearate, glyceryl triacetate, which are dissolved in absolute ethyl alcohol, to be configured to
30% coating solution takes intermittent spray operation in rolling seed-coating machine, and alternately with drying, atomizing pressure is for spraying
2.5kg/cm2, 45 DEG C of inlet air temperature, hydrojet speed 2mL/min needs to continuously stir coating solution in coating process；
Flora trigger layer is coated：Alginate, EudragitRL30D, magnesium stearate, glyceryl triacetate are dissolved in anhydrous
15% coating solution is configured in ethyl alcohol, coating method is identical as PH control layer coating operations.
Colon slow-releasing pill obtained is poured by each Capsules dress 0.2g in Capsules and is got product.
The preparation of 4 degree of drawing glycopeptide site specific DDS for colon slow-releasing pills of embodiment
Capsule core prescription：
Slow release layer prescription：
Sodium carboxymethylcellulose 18.9g
Tartaric acid 4.9g
Sodium chloride 3.2g
PH control layer prescriptions：
Eudragit FS 24.3g
Magnesium stearate 10.1g
Methyl hydroxybenzoate 6.1g
Flora trigger layer prescription：
Preparation process：
Pellet core：Glycopeptide, starch, sodium carboxymethyl starch and hydroxypropyl methyl cellulose is drawn to be dissolved in 95% ethyl alcohol degree molten
It is uniformly mixed in liquid, the blank capsule core 500g for weighing 45 mesh is placed in fluid bed, and drug solution spraying is wrapped in blank capsule core
On, it prepares and carries pill core；
Slow release layer is coated：Sodium carboxymethylcellulose, tartaric acid, sodium chloride are dissolved in be configured in absolute ethyl alcohol 15% packet
Clothing liquid is sprayed using side spray mode to piece wicking surface in rolling seed-coating machine, 3 hours dry in 45 DEG C of electric drying oven with forced convections；
PH control layers are coated：Eudragit FS, magnesium stearate and methyl hydroxybenzoate, which are dissolved in absolute ethyl alcohol, is configured to 25%
Coating solution, take intermittent spray operation in rolling seed-coating machine, spraying with it is dry alternately, atomizing pressure 4.0kg/
cm2, 60 DEG C of inlet air temperature, hydrojet speed 2mL/min needs to continuously stir coating solution in coating process；
Flora trigger layer is coated：Chitosan, EudragitRL30D, medicinal talcum powder and dibutyl phthalate is molten
15% coating solution is configured in absolute ethyl alcohol, coating method is identical as PH control layer coating operations.
The preparation of 5 degree of drawing glycopeptide colon-targeted sustained-release tablets of embodiment
Capsule core prescription：
Slow release layer prescription：
Ethyl cellulose 16.8g
Polyethylene glycol 4.2g
Potassium hydrogen phosphate 7.0g
PH control layer prescriptions：
Eudragit E 39.2g
Magnesium stearate 5.6g
Triethyl citrate 11.2g
Flora trigger layer prescription：
Preparation process：
Drug containing label：Degree draws glycopeptide, mannitol, hydroxypropyl methyl cellulose to be uniformly mixed using the method for equal increments,
It sieves with 100 mesh sieve, softwood is made in the cmc soln that absolute ethyl alcohol dissolving is added, and crosses 24 mesh sieve, pelletizes, 55 in fluid bed
DEG C dry 2h, crosses 40 mesh sieves, tabletting；
Slow release layer is coated：Ethyl cellulose, polyethylene glycol and potassium hydrogen phosphate are dissolved in absolute ethyl alcohol and are configured to 10%
Coating solution is sprayed using side spray mode to piece wicking surface in rolling seed-coating machine, and dry 3 is small in 50 DEG C of electric drying oven with forced convections
When；
PH control layers are coated：Eudragit E, magnesium stearate and triethyl citrate are dissolved in absolute ethyl alcohol and are configured to
25% coating solution takes intermittent spray operation in rolling seed-coating machine, and alternately with drying, atomizing pressure is for spraying
4.0kg/cm2, 55 DEG C of inlet air temperature, hydrojet speed 2.5mL/min needs to continuously stir coating solution in coating process.
Flora trigger layer is coated：Guar gum, EudragitRL30D, medicinal talcum powder and glyceryl triacetate are dissolved in nothing
18% coating solution is configured in water-ethanol, coating method is identical as PH control layer coating operations.
Degree is made and draws glycopeptide colon-targeted sustained-release tablets agent 1000.
The preparation of 6 degree of drawing glycopeptide site specific DDS for colon spansule of embodiment
Core formulation：
Slow release layer prescription：
Chitin 21.5g
Citric acid 14.0g
Disodium hydrogen phosphate 11.2g
PH control layer prescriptions：
III 25.7g of acrylic resin
Glycerin monostearate 9.4g
Triethyl citrate 11.7g
Flora trigger layer prescription：
Preparation process：
Pellet core：Glycopeptide, dextrin, polyvinylpyrrolidone and sodium carboxymethyl starch is drawn to be dissolved in 90% ethanol solution degree
In be uniformly mixed, the blank capsule core 500g for weighing 60 mesh is placed in fluid bed, by drug solution spraying be wrapped in blank capsule core,
It prepares and carries pill core；
Slow release layer is coated：Chitin, citric acid and disodium hydrogen phosphate are dissolved in be configured in absolute ethyl alcohol 20% coating
Liquid is sprayed using side spray mode to piece wicking surface in rolling seed-coating machine, 3 hours dry in 45 DEG C of electric drying oven with forced convections；
PH control layers are coated：Acrylic resin III, glycerin monostearate and triethyl citrate are dissolved in absolute ethyl alcohol
In be configured to 35% coating solution, take intermittent spray operation in rolling seed-coating machine, spraying with it is dry alternately, atomization
Pressure is 4.5kg/cm2, 45 DEG C of inlet air temperature, hydrojet speed 3mL/min needs to continuously stir coating solution in coating process；
Flora trigger layer is coated：Chitosan, EudragitRL30D, magnesium stearate and glyceryl triacetate are dissolved in anhydrous
20% coating solution is configured in ethyl alcohol, coating method is identical as PH control layer coating operations.
Colon slow-releasing pill obtained is poured by each Capsules dress 0.26g in Capsules and is got product.
The preparation of 7 degree of drawing glycopeptide colon-targeted sustained-release tablets agent of embodiment
Core formulation：
Slow release layer prescription：
Polyvinyl alcohol 31.3g
Polyethylene glycol 14.5g
Xylose 12.2g
PH control layer prescriptions：
Eudragit L100 26.7g
Magnesium stearate 14.5g
Methyl hydroxybenzoate 16.8g
Flora trigger layer prescription：
Preparation process：
Drug containing label：Glycopeptide, mannitol, crosslinked polyvinylpyrrolidone is drawn to be mixed using the method for equal increments degree
It is even, it sieves with 100 mesh sieve, softwood is made in the Gonak that absolute ethyl alcohol dissolving is added, and crosses 24 mesh sieve, pelletizes, stream
Change 55 DEG C of dry 2h in bed, crosses 40 mesh sieves, tabletting；
Slow release layer is coated：Polyvinyl alcohol, polyethylene glycol and xylose are dissolved in be configured in absolute ethyl alcohol 10% coating solution,
It is sprayed to piece wicking surface using side spray mode in rolling seed-coating machine, it is 4 hours dry in 50 DEG C of electric drying oven with forced convections；
PH control layers are coated：Eudragit L100, magnesium stearate and methyl hydroxybenzoate are dissolved in absolute ethyl alcohol and are configured to
25% coating solution takes intermittent spray operation in rolling seed-coating machine, and alternately with drying, atomizing pressure is for spraying
4.5kg/cm2, 50 DEG C of inlet air temperature, hydrojet speed 2mL/min needs to continuously stir coating solution in coating process.
Flora trigger layer is coated：Chitosan, EudragitRL30D, magnesium stearate and triethyl citrate are dissolved in anhydrous
15% coating solution is configured in ethyl alcohol, coating method is identical as PH control layer coating operations.
Degree is made and draws glycopeptide colon-targeted sustained-release tablets agent 1000.
8 degree of embodiment draws the preparation of glycopeptide site specific DDS for colon sustained release ball
Capsule core prescription：
Slow release layer prescription：
Hyetellose 31.9g
Polyethylene glycol 5.4g
Dibastic sodium phosphate 7.7g
PH control layer prescriptions：
Eudragit L100 26.1g
Magnesium stearate 8.6g
Diethyl phthalate 10.4g
Flora trigger layer prescription：
Preparation process：
Pellet core：It draws glycopeptide, starch, carboxymethyl cellulose and microcrystalline cellulose to be dissolved in 95% ethanol solution degree to mix
It closes uniformly, the blank capsule core 500g for weighing 45 mesh is placed in fluid bed, and drug solution spraying is wrapped in blank capsule core, is prepared
Carry pill core；
Slow release layer is coated：Hyetellose, polyethylene glycol and dibastic sodium phosphate are dissolved in absolute ethyl alcohol and are configured to 20%
Coating solution is sprayed using side spray mode to piece wicking surface in rolling seed-coating machine, and dry 3 is small in 45 DEG C of electric drying oven with forced convections
When；
PH control layers are coated：Eudragit L100, magnesium stearate and diethyl phthalate are dissolved in absolute ethyl alcohol
It is configured to 20% coating solution, intermittent spray operation is taken in rolling seed-coating machine, alternately with drying, atomization is pressed for spraying
Power is 4.5kg/cm2, 55 DEG C of inlet air temperature, hydrojet speed 2mL/min needs to continuously stir coating solution in coating process；
Flora trigger layer is coated：Chitosan, EudragitRL30D, medicinal talcum powder and methyl hydroxybenzoate are dissolved in anhydrous
15% coating solution is configured in ethyl alcohol, coating method is identical as PH control layer coating operations.
The preparation of 9 degree of drawing glycopeptide colon-targeted sustained-release tablets of embodiment
Capsule core prescription：
Slow release layer prescription：
Hydroxypropyl methylcellulose 26.8g
Tartaric acid 7.8g
Potassium chloride 8.6g
PH control layer prescriptions：
Eudragit S100 28.1g
Magnesium stearate 10.8g
Glyceryl triacetate 4.3g
Flora trigger layer prescription：
Preparation process：
Drug containing label：Glycopeptide, microcrystalline cellulose, crosslinked polyvinylpyrrolidone is drawn to be mixed using the method for equal increments degree
It closes uniformly, softwood is made in the Gonak that addition is dissolved in water, crosses 24 mesh sieve, and granulation is placed in 50 DEG C of baking ovens
40 mesh sieves, tabletting are crossed in drying；
Slow release layer is coated：Hydroxypropyl methylcellulose, tartaric acid, potassium chloride are dissolved in be configured in absolute ethyl alcohol 20% coating
Liquid is sprayed using side spray mode to piece wicking surface in rolling seed-coating machine, 4 hours dry in 50 DEG C of electric drying oven with forced convections；
PH control layers are coated：Eudragit S100, magnesium stearate, glyceryl triacetate are dissolved in absolute ethyl alcohol and prepared
At 30% coating solution, intermittent spray operation is taken in rolling seed-coating machine, alternately with drying, atomizing pressure is for spraying
4.5kg/cm2, 50 DEG C of inlet air temperature, hydrojet speed 2mL/min needs to continuously stir coating solution in coating process；
Flora trigger layer is coated：Chitosan, EudragitRS30D, talcum powder, methyl hydroxybenzoate are dissolved in absolute ethyl alcohol
It is configured to 15% coating solution, is placed in rolling seed-coating machine and is coated, it is 5 hours dry in 50 DEG C of electric drying oven with forced convections.
The preparation of 10 degree of drawing glycopeptide colon-targeted sustained-release tablets of embodiment
Capsule core prescription：
Slow release layer prescription：
Ethyl cellulose 35.2g
Polyethylene glycol 16.0g
Potassium chloride 12.8g
PH control layer prescriptions：
II 48.0g of acrylic resin
Glycerin monostearate 6.4g
Triethyl citrate 9.6g
Flora trigger layer prescription：
Preparation process：
Drug containing label：Glycopeptide, starch, crosslinked polyvinylpyrrolidone is drawn to be mixed using the method for equal increments degree
It is even, it sieves with 100 mesh sieve, softwood is made in the Gonak that absolute ethyl alcohol dissolving is added, and crosses 24 mesh sieve, pelletizes, stream
Change 55 DEG C of dry 2h in bed, crosses 40 mesh sieves, tabletting；
Slow release layer is coated：Poly- ethyl cellulose, polyethylene glycol and potassium chloride are dissolved in absolute ethyl alcohol and are configured to 10%
Coating solution is sprayed using side spray mode to piece wicking surface in rolling seed-coating machine, and dry 4 is small in 50 DEG C of electric drying oven with forced convections
When；
PH control layers are coated：Acrylic resin II, glycerin monostearate and triethyl citrate are dissolved in absolute ethyl alcohol
In be configured to 25% coating solution, take intermittent spray operation in rolling seed-coating machine, spraying with it is dry alternately, atomization
Pressure is 4.5kg/cm2, 50 DEG C of inlet air temperature, hydrojet speed 1.5mL/min needs to continuously stir coating solution in coating process.
Flora trigger layer is coated：Chitosan, EudragitRL30D, magnesium stearate and methyl hydroxybenzoate are dissolved in anhydrous second
15% coating solution is configured in alcohol, coating method is identical as PH control layer coating operations.
Degree is made and draws glycopeptide colon-targeted sustained-release tablets agent 1000.
11 extracorporeal releasing experiment of embodiment
It weighs appropriate above-described embodiment 1, embodiment 2, embodiment 3, embodiment 7, embodiment 10 degree obtained and draws glycopeptide knot
Intestines positioning and slow release preparation first dissolves out 2h respectively in the artificial simulation gastric juices of pH1.2, then changes manual simulation's intestinal fluid into respectively
PH6.8 buffer solutions dissolve out 3 hours, and the buffer solution for being then respectively placed in manual simulation's colonic fluid pH7.2 carries out dissolution investigation.With height
Effect liquid phase chromatogram method calculates cumulative release percentage, with release time (h) and cumulative release amount (%), draws release profiles.Knot
Fruit is as shown in Figure 1.
Acetonideexample 1, embodiment 2, embodiment 3, embodiment 7, embodiment 10 sample in gastric juice and intestinal fluid without releasing
It puts, then starts to discharge in the buffer solution of manual simulation's colonic fluid pH7.2, and sustained release is complete.
Claims (17)
1. a kind of degree draws glycopeptide site specific DDS for colon sustained release preparation, which is characterized in that its by label or capsule core, slow release layer, pH control layers,
Flora trigger layer forms；
The degree is drawn in glycopeptide site specific DDS for colon sustained release preparation, and by weight, drug containing label or capsule core account for 30~60%, slow release layer and account for
15~30%, pH control layer account for 10~30%, and flora trigger layer accounts for 15~40%；
The label or capsule core include that main ingredient degree draws glycopeptide, diluent, binder and disintegrant；The slow release layer includes sustained release material
Material, plasticizer and pore-foaming agent；The pH control layers include enteric material, antiplastering aid and plasticizer；The flora trigger layer includes
Flora triggers material, bleeding agent, antiplastering aid and plasticizer；
The slow-release material is selected from ethyl cellulose, sodium alginate, tragacanth, methylcellulose, hyetellose, hydroxypropyl first
In cellulose, hydroxypropyl second cellulose, sodium carboxymethylcellulose, chitin, galactomannan, polyvinyl alcohol, carbopol
It is one or more；
The enteric material is selected from Eudragit L100, Eudragit S100, Eudragit FS, Eudragit E, acrylic acid
It is one or more in resin II, acrylic resin III；
The flora triggering material is one or more in chitosan, alginate, pectin, guar gum.
2. site specific DDS for colon sustained release preparation according to claim 1, which is characterized in that the label or capsule core are by 10~50%
Main ingredient degree draw glycopeptide, 5~20% diluent, 10~30% binder and 15~40% disintegrants composition.
3. site specific DDS for colon sustained release preparation according to claim 1, which is characterized in that diluted described in the label or capsule core
Agent is one or more in starch, microcrystalline cellulose, mannitol, dextrin.
4. site specific DDS for colon sustained release preparation according to claim 1, which is characterized in that binded described in the label or capsule core
Agent is selected from one in polyvinylpyrrolidone (PVP), polyethylene glycol, starch slurry, carboxymethyl cellulose, hydroxypropyl methyl cellulose
Kind is a variety of.
5. site specific DDS for colon sustained release preparation according to claim 1, which is characterized in that be disintegrated described in the label or capsule core
Agent in crosslinked polyvinylpyrrolidone, sodium carboxymethyl starch, starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose one
Kind is a variety of.
6. site specific DDS for colon sustained release preparation according to claim 1, which is characterized in that the slow release layer by 40~80% it is slow
Release material, 5~35% the plasticizers and 5~35% pore-foaming agent composition.
7. site specific DDS for colon sustained release preparation according to claim 1, which is characterized in that plasticizer described in the slow release layer selects
From one or more in polyethylene glycol, tartaric acid, citric acid.
8. site specific DDS for colon sustained release preparation according to claim 1, which is characterized in that pore-foaming agent described in the slow release layer selects
From one kind in starch, xylose, potassium chloride, sodium chloride, dibastic sodium phosphate, potassium hydrogen phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate or more
Kind.
9. site specific DDS for colon sustained release preparation according to claim 1, which is characterized in that the pH control layers are by 30~80%
Enteric material, 8~30% antiplastering aid and 8~30% plasticizer composition.
10. site specific DDS for colon sustained release preparation according to claim 1, which is characterized in that resist described in the pH control layers glutinous
Agent is one or more in talcum powder, magnesium stearate, glycerin monostearate.
11. site specific DDS for colon sustained release preparation according to claim 1, which is characterized in that be plasticized described in the pH control layers
Agent is selected from diethyl phthalate, dibutyl phthalate, triethyl citrate, glyceryl triacetate, methyl hydroxybenzoate
In it is one or more.
12. site specific DDS for colon sustained release preparation according to claim 1, which is characterized in that the flora trigger layer by 40~
75% flora triggering material, 5~25% bleeding agents, 5~15% antiplastering aids and 5~20% plasticizer composition.
13. site specific DDS for colon sustained release preparation according to claim 1, which is characterized in that oozed described in the flora trigger layer
Saturating agent is one or more in Eudragit RL30D, Eudragit RS30D, Eudragit NE, Eudragit NM.
14. site specific DDS for colon sustained release preparation according to claim 1, which is characterized in that resist described in the flora trigger layer
Glutinous agent is one or more in medicinal talcum powder, magnesium stearate, glycerin monostearate.
15. site specific DDS for colon sustained release preparation according to claim 1, which is characterized in that increase described in the flora trigger layer
It moulds agent and is selected from diethyl phthalate, dibutyl phthalate, triethyl citrate, glyceryl triacetate, Metagin
It is one or more in ester.
16. site specific DDS for colon sustained release preparation according to claim 1, which is characterized in that it is tablet, capsule or pill.
17. a kind of degree draws the preparation method of glycopeptide site specific DDS for colon sustained release preparation, which is characterized in that include the following steps：
1) prepared by label or capsule core
It is prepared by label：It draws glycopeptide, diluent and disintegrant to be uniformly mixed main ingredient degree, adhesive is added, softwood, sieving system is made
Grain, drying, whole grain of being sieved, tabletting keep hardness in 50.0 ± 6.3N/cm when tabletting2In range；
It is prepared by capsule core：Using blank capsule core as carrier, solution or suspension is made in drug, makes drug solution in a fluidized bed
Spraying is wrapped in blank capsule core, is prepared and is carried pill core；
2) slow release layer is coated：Drug containing label obtained in 1) or capsule core are used in rolling seed-coating machine with slow release layer Coating Solution
Side spray mode is sprayed to label or capsule core surface, 3~5 hours dry in 45~60 DEG C of electric drying oven with forced convections；
3) pH control layers are coated：Sustained release label obtained in 2) or capsule core are passed through into spraying-rolling with pH control layers Coating Solution
Coating method or fluidized bed coating are coated, and are sprayed with drying alternately, 0.5~5kg/cm of atomizing pressure2, inlet air temperature
45~60 DEG C, 1.5~3mL/min of hydrojet speed；
4) flora trigger layer is coated：PH control layers label obtained in 3) or capsule core are passed through into spraying-with flora trigger layer solution
Turnadle pan coating or fluidized bed coating are coated, and are sprayed with drying alternately, 0.5~5kg/cm of atomizing pressure2, air inlet
45~60 DEG C of temperature, 1.5~3mL/min of hydrojet speed.
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| WO2018090266A1 (en) * | 2016-11-17 | 2018-05-24 | 上海交通大学医学院 | Oral colon-targeted delivery system and preparation method and application thereof |
| CN109846043B (en) * | 2017-11-30 | 2023-04-07 | 内蒙古伊利实业集团股份有限公司 | Colon slow-release probiotics and preparation method thereof |
| CN108157978A (en) * | 2017-12-30 | 2018-06-15 | 上海健煌生物科技有限公司 | A kind of peptide composition of adjusting intestinal flora containing burdock polysaccharide and application |
| CN108201140A (en) * | 2018-01-31 | 2018-06-26 | 无限极（中国）有限公司 | A kind of walnut peptide colon-specific pellets and preparation method thereof |
| EP3662902A1 (en) * | 2018-12-07 | 2020-06-10 | Tillotts Pharma AG | Colonic drug delivery formulation |
| CN110974943A (en) * | 2019-12-09 | 2020-04-10 | 广东药科大学 | Oral insulin pharmaceutical preparation and preparation method thereof |
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