CN105902500A - Mesalazine enteric positioned controlled-release preparation and preparation method thereof - Google Patents
Mesalazine enteric positioned controlled-release preparation and preparation method thereof Download PDFInfo
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- CN105902500A CN105902500A CN201610269892.4A CN201610269892A CN105902500A CN 105902500 A CN105902500 A CN 105902500A CN 201610269892 A CN201610269892 A CN 201610269892A CN 105902500 A CN105902500 A CN 105902500A
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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
- A61K31/60—Salicylic acid; Derivatives thereof
- A61K31/606—Salicylic acid; Derivatives thereof having amino groups
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- 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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- A61K9/00—Medicinal preparations characterised by special physical form
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
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Abstract
The invention discloses mesalazine enteric positioned controlled-release preparation, comprising a core, a controlled-release coating layer, an adhesive coating layer, and an enteric coating layer. The core includes mesalazine, hydroxyl propyl cellulose and talc powder, the controlled-release coating layer is composed of ethyl cellulose and triethyl citrate, the adhesive coating layer is made from sodium alginate, the enteric coating layer is composed of methacrylic acid and methyl methacrylate copolymer, triethyl citrate and talc powder. The invention also provides a preparation method of the enteric positioned controlled-release preparation. The preparation method is simple with controllable parameters, prepared pellets do not release in gastric acid and may release slowly for 24 hours in a dissolution medium at pH 7.5. This preparation is irritating to gastrointestinal adhesion and may be used in acute stage treatment for ulcerative colitis (inflammation accompanied ulcers) and maintenance treatment for preventing recurrence.
Description
Technical field
The invention belongs to field of medicaments, relate to a kind of slow releasing preparation, specifically a kind of mesalazine enteric location control
Release formulation and preparation method thereof.
Background technology
Mesalazine is the active component of sulfasalazine, according to clinical effectiveness, the therapeutical effect after oral this product with
Rectally is similar, for local action, is used for treating the acute stages treated of ulcerative colitis (inflammation companion's ulcer) and prevention is multiple
The maintaining treatment sent out and the symptom of activeness Crohn disease improve treatment.Mesalazine in vivo, external all can suppress white carefully
Born of the same parents' chemotactic, reduction cytokine and leukotriene produce, remove free radical.Existing research shows, mesalazine is to experimental animal
There is nephrotoxicity.Shown by the pharmacology of mesalazine, preferable drug release position should at diseased region colon,
Stomach and the medicine of small intestine site release, be rapidly absorbed into body circulation, lessen the curative effect on the contrary and bring the side effect such as nephrotoxicity.
It is suitable for making colon adhesion location since Jindrich Kopecek etc. proposes mesalazine in the nineties in last century
After release preparation [Kopecek, J.Journal of Controlled Release 1990,11 (1-3): 279～290]
[Kopecek,J.H.R.Journal of Controlled Release 1992,19(1-3):
121～130], having carried out a series of research for mesalazine dosage form, the dosage form listed includes enteric coatel tablets (glue
Capsule), slow releasing tablet (capsule), suppository, enteric controlled-release capsule etc..Due to Human Physiology condition, colon site is (under particularly
Portion) body fluid is less, is not appropriate for drug release, and therefore preferably administering mode is that preparation adheres to be positioned colon upper end, medicine
Slowly release reaches diseased region performance curative effect.Mesalazine is had to adhere to dosage form research [the Tereza B.Miloslava of location
R.Arnaud B.European Journal of Pharmaceutics and Biopharmaceutics 2012,81:379
～385] [C.Mura, A.N á cher, V.Merino.Colloids and Surfaces B:Biointerfaces 2012,
94:199～205], but there is the deficiencies such as mesalazine drug loading is the highest, the control of industrialization preparation parameter is complicated in the studies above, separately
Outward, patient needs to take mesalazine for a long time throughout the year, as adhesion material conventional in adhesion preparation to gastrointestinal tract mucous thorn
Swashing property and toxicity is a key issue that can not ignore, studies have reported that, mucosa can be produced by some adhesion material to stimulate
Property [Yang Chunli, Ma Jing. " Chinese Journal of Pharmaceuticals " 2000,11:490～491] [Lv Yi, Wu Canrong, Tan Hanyu. " in Hunan
Medical pharmaceutical university journal " 2009,1:38～40], the zest of mucosa can be increased the weight of suffer from colonic ulcer by adhesion material further
The state of an illness of patient.For the treatment of patients of ulcerative colitis, position at colon site in the urgent need to one clinically, gently
Release, the conlon targeting slow releasing preparation that gastrointestinal tract is had no stimulation.
Summary of the invention
For above-mentioned technical problem of the prior art, the invention provides a kind of mesalazine enteric positioning controlled-release preparation
And preparation method thereof, described this mesalazine enteric positioning controlled-release preparation and preparation method thereof to solve of the prior art
Gastrointestinal tract mucous generation zest and toxicity can be increased the weight of the technology suffering from the state of an illness of colonic ulcers by mesalazine preparation
Problem.
The invention provides a kind of mesalazine enteric positioning controlled-release preparation, it is characterised in that: the most successively by interior
Core, controlled release coating layer, adhesion coatings, enteric coat layer form, containing mesalazine, hydroxypropyl cellulose in described inner core
And Pulvis Talci, described controlled release coating layer is made up of ethyl cellulose, triethyl citrate, and described adhesion coatings uses sea
Sodium alginate, described enteric coat layer is by methacrylic acid and methylmethacrylate copolymer, triethyl citrate and Talcum
Powder forms, and the percentage by weight of each composition consists of as follows:
Diameter of aspirin particle≤200 μm of described mesalazine；Hydroxypropyl cellulose is when mass percent concentration is 2%
Viscosity is 4000～6500mPa s, mean molecule quantity 850000；Ethyl cellulose viscosity is when mass percent concentration is 5%
Viscosity be 6～16mPa s, ethyl substitution value 48.0～49.5；Sodium alginate mean molecule quantity 5000～15000；Methyl-prop
Olefin(e) acid is with methylmethacrylate copolymer, and methacrylic acid is 1:1 or 1:2 copolymerization with the mol ratio of methyl methacrylate
Thing.
Further, the percentage by weight of each composition consists of as follows:
Further, it is also possible to containing excipient and lubricant.
Further, described excipient be in lactose, mannitol, microcrystalline Cellulose any one or two or more
Combination；Described lubricant be in magnesium stearate, stearic acid, Pulvis Talci, micropowder silica gel, Polyethylene Glycol any one or
Two or more combinations.
Further, described inner core is made up of mesalazine, lactose, hydroxypropyl cellulose and Pulvis Talci, each composition
Percentage by weight consist of as follows:
Mesalazine diameter of aspirin particle≤200 μm；Hydroxypropyl cellulose is that viscosity when 2% is at mass percent concentration
4000～6500, mean molecule quantity 850000；Ethyl cellulose viscosity mass percent concentration be viscosity when 5% be 6～
8, ethyl substitution value 48.0～49.5；Sodium alginate mean molecule quantity 10000；Wherein methacrylic acid and methyl methacrylate
Copolymer is the copolymer of ratio 1:2.
Further, its dosage form is micropill.
Present invention also offers the preparation method of above-mentioned a kind of mesalazine enteric positioning controlled-release preparation, including making as follows
Standby step:
1) each supplementary material is weighed according to mass percent；
2) step preparing mesalazine pastille micropill；Mesalazine is crossed screen cloth, makes drug microparticles volume average
Particle diameter≤200 μm；Again by after in capsule core, 60 eye mesh screens crossed by other adjuvant, mix with mesalazine；Take said mixture and put fluidisation
In Chuan, carrying out fluidized granulation with alcohol-water solvent, the volume ratio of second alcohol and water is 60～80:30, and solvent controls fluidized-bed temperature
40～50 DEG C, 40 mesh granulate after particle drying, screening 40～60 mesh granules as parent nucleus, put micropill processed in WL-300 pellet processing machine,
Control rotary speed 200～300rpm, inlet temperature 35～45 DEG C, prepare pastille micropill, control micropill diameter 0.8～
1.5mm；By prepared micropill and the Pulvis Talci mixing in inner core, standby；
3) step preparing mesalazine controlled release micro pill；Ethyl cellulose is added in ethanol, prepare percent mass
Specific concentration is the ethanol solution of ethyl cellulose of 1～2.5%, adds the triethyl citrate in controlled release coating layer, stirs molten
Solve, the mesalazine pastille micropill that step (1) is obtained, put bag ethylcellulose in LBL-3 type fluid bed, control air intake temperature
Spend 35～45 DEG C, air pressure≤0.5MPa, obtain mesalazine controlled release micro pill；
4) step preparing mesalazine adhesion controlled release micro pill；Sodium alginate is added to the water, is configured to quality hundred
Proportion by subtraction concentration is the sodium alginate aqueous solution of 0.8～1.2%, micropill step (2) obtained, and puts in LBL-3 type fluid bed and wraps
Sodium alginate layer, control inlet temperature 35～45 DEG C, air pressure≤0.5MPa, obtain mesalazine and adhere to controlled release micro pill；
5) step preparing mesalazine enteric controlled-release micropill；By methacrylic acid and methyl methacrylate copolymer
Enteric layer coating solution is made after triethyl citrate in thing, enteric coat layer and the mixing of the Pulvis Talci in enteric coat layer, will
The mesalazine pastille micropill that step (3) obtains, puts bag enteric layer in LBL-3 type fluid bed, controls inlet temperature 35～45 DEG C,
Air pressure≤0.5MPa, obtains mesalazine enteric controlled-release micropill.
Further, in alcohol-water solvent, the volume ratio of second alcohol and water is 70:30.
The mesalazine enteric positioning controlled-release preparation of the present invention is by pastille skeleton capsule core, slow release, adhesion and enteric coat layer
Composition, by hydroxypropyl cellulose as framework material, prepares micropill by ethylcellulose coat (water-insoluble material), sea
After sodium alginate coating (adhesion material) and methacrylic acid and methylmethacrylate copolymer coating, at animal large intestine epimere
It is detained the long period, releases in location, colon portion.Preparation not release under the conditions of gastric acid, can put down under the conditions of pH7.5 dissolution medium
Steady release 24 hours.
The present invention compares with prior art, and its technological progress is significant.The preparation method of the present invention is easy, parameter can
Control.Invention formulation adheres to do not have zest to gastrointestinal tract, may be used for treating the urgency of ulcerative colitis (inflammation companion's ulcer)
Property the phase treat and prevent recurrence maintaining treatment and activeness Crohn disease symptom improve treatment.
Accompanying drawing explanation
Fig. 1 shows the drug release in vitro degree of embodiment 1,3～6 micropill sample.
Detailed description of the invention
It is further elucidated with present disclosure below in conjunction with embodiment, but is not limiting as the present invention.
The drug release in vitro degree of mesalazine enteric positioning controlled-release preparation of the present invention, micropill acid resisting test, microsphere
The research methoies such as gastrointestinal retentiveness rate, mucous membrane irritation are as follows:
Drug release in vitro degree assay method: be placed in by micropill and turn in basket, according to Chinese Pharmacopoeia drug release determination method (China
2010 editions two annex XC of pharmacopeia) the first subtraction unit, pH1 hydrochloric acid solution 1000ml is solvent, and rotating speed is 100 turns per minute, depends on
Method operates, and takes out micropill, distilled water wash micropill, is immediately placed in phosphate buffer (pH7.5) 1000ml solvent, turn after 2h
Speed is 100 turns per minute, operates in accordance with the law, respectively 2.5,4h, 6h, 8h, 10h, 12h, 16h, 20h and 24h be (under the conditions of containing pH1 2
Hour dissolution time) sampling 10ml, and supplement rapidly 37 DEG C of solvent 10ml, and filtering, precision measures filtrate 2ml, puts 25ml measuring bottle
In, solubilizer is diluted to scale, shakes up, as need testing solution；Separately take mesalazine reference substance appropriate, make with solvent dilution
20 μ g/ml solution, as reference substance solution, measure above-mentioned solution absorbance value at 330nm respectively, calculate the medicine of different time
Thing burst size.
Micropill acid resisting test: be placed in by micropill and turn in basket, according to Chinese Pharmacopoeia drug release determination method (Chinese Pharmacopoeia 2010
Two annex XC of version) the first subtraction unit, pH1 hydrochloric acid solution 1000ml is solvent, and rotating speed is 100 turns per minute, operates, 2h in accordance with the law
Rear taking-up micropill, distilled water wash micropill surface, micropill is put in mortar finely ground, be transferred in 250ml measuring bottle, add pH7.5 phosphorus
Hydrochlorate solvent is appropriate, and ultrasonic disperse 30min lets cool, is settled to scale, filters, takes filtrate and be diluted to about 20 μ g/ml solution,
Survey absorbance at 330nm, calculate residual drug amount in micropill, micropill Chinese medicine under the conditions of pH1 hydrochloric acid burst size should≤
10%.
Micropill gastrointestinal retentiveness rate: SD rat 40, body weight 300～350g, it is divided into four groups, fasting is supplied water after raising 12h,
Give micropill.It is the plastic tube of 3.5mm with internal diameter, an end closure, loading particle diameter is 1000～2500 μm micropill 100, another
Termination 5ml syringe, inserts sealing end plastic tube in rat stomach, is poured in rat stomach by microsphere with 2ml normal saline.Gavage
After micropill, water is prohibited in fasting, and the neck that breaks in time gavaging 2h, 4h, 7h and 12h after test puts to death rat, takes small intestinal, large intestine is cut off, and
Large intestine is divided equally into upper, middle and lower segment, the micropill number in counting stomach, small intestinal and each section of large intestine, calculates each phase micropill and be detained
Percentage rate.
Adhesion material mucous membrane irritation: 12 KM mices (female, 20～30g/ only), is randomly divided into 4 groups, carbomer, sea
Sodium alginate isogel vagina administration, is inverted mice 1 minute after administration, and medicinal liquid is fully contacted with mucosa, puts to death dynamic after 24 hours
Thing, observes mucosa with or without the phenomenon such as congested, red and swollen.
Embodiment 1
| Inner core: | |
| Mesalazine | 66.7% |
| Lactose | 5.8% |
| Hydroxypropyl cellulose (Klucel MF) | 9.2% |
| Pulvis Talci | 1.6% |
| Controlled release coating layer: | |
| Ethyl cellulose (AqualonTM N7) | 2.4% |
| Triethyl citrate | 0.3% |
| Adhesion coatings: | |
| Sodium alginate (mean molecule quantity 10000) | 5.0% |
| Enteric coat layer: | |
| Especially strange S100 | 7.2% |
| Triethyl citrate | 0.7% |
| Pulvis Talci | 1.1% |
The preparation method of above-mentioned mesalazine enteric positioning controlled-release preparation is as follows:
(1) prepared by mesalazine pastille micropill
Take percentage by weight to consist of the mesalazine of 66.7% and cross 80 eye mesh screens, make drug microparticles volume average particle size≤
200μm；Take again percentage by weight consist of 9.2% hydroxypropyl cellulose (Klucel MF) and percentage by weight consist of
After 60 eye mesh screens crossed by the lactose of 5.8%, mix with mesalazine；Take above-mentioned spiece and put in fluid bed, use alcohol-water
(70:30) solvent carries out fluidized granulation, controls fluidized-bed temperature 45 DEG C, 40 mesh granulate after particle drying, screens 40～60 mesh
Grain as parent nucleus, micropill processed in WL-300 pellet processing machine, control rotary speed 200～300rpm, inlet temperature 40 DEG C, prepare
Pastille micropill, controls micropill diameter 0.8～1.5mm；Prepared micropill is mixed with Pulvis Talci, standby；
(2) prepared by mesalazine controlled release micro pill
Preparation mass percent concentration is the ethyl cellulose ethanol solution of 2.4%, and adding mass percent is 0.3% lemon
Lemon triethylenetetraminehexaacetic acid ester, after stirring and dissolving, the mesalazine pastille micropill that step (1) is obtained, put Bao Yi in LBL-3 type fluid bed
Base cellulose layer, controls inlet temperature 40 DEG C, air pressure≤0.5MPa, obtains mesalazine controlled release micro pill.
(3) prepared by mesalazine adhesion controlled release micro pill
Prepare 1% sodium alginate aqueous solution, weigh the sodium alginate aqueous solution of mass percent 5% by recipe quantity, will step
Suddenly the micropill that (2) obtain, puts bag sodium alginate layer in LBL-3 type fluid bed, controls inlet temperature 40 DEG C, and air pressure≤
0.5MPa, obtains mesalazine and adheres to controlled release micro pill.
(4) prepared by mesalazine enteric positioning controlled-release micropill
Preparation enteric layer coating solution is (containing mass percent 7.2% especially strange S100,0.7% triethyl citrate and 1.1%
Pulvis Talci), the micropill that step (3) is obtained, put bag enteric layer in LBL-3 type fluid bed, control inlet temperature 40 DEG C, air pressure
Power≤0.5MPa, obtains mesalazine enteric positioning controlled-release micropill.
Embodiment 2
| Inner core: | |
| Mesalazine | 66.7% |
| Lactose | 10.8% |
| Hydroxypropyl cellulose (Klucel MF) | 9.2% |
| Pulvis Talci | 1.6% |
| Controlled release coating layer: | |
| Ethyl cellulose (AqualonTM N7) | 2.4% |
| Triethyl citrate | 0.3% |
| Enteric coat layer: | |
| Especially strange S100 | 7.2% |
| Triethyl citrate | 0.7% |
| Pulvis Talci | 1.1% |
The preparation method of above-mentioned mesalazine enteric controlled-release preparation is as follows:
(1) prepared by mesalazine pastille micropill
Take mass percent to consist of the mesalazine of 66.7% and cross 80 eye mesh screens, make drug microparticles volume average particle size≤
200μm；Take mass percent again and consist of the hydroxypropyl cellulose of 9.2% and after the lactose of 10.8% crosses 60 eye mesh screens, with U.S.
Salad piperazine mixes；Take above-mentioned spiece and put in fluid bed, carry out fluidized granulation with alcohol-water (70:30) solvent, control stream
Changing bed tempertaure 45 DEG C, 40 mesh granulate after particle drying, screening 40～60 mesh granules, as parent nucleus, are made micro-in WL-300 pellet processing machine
Ball, controls rotary speed 200～300rpm, inlet temperature 40 DEG C, prepares pastille micropill, control micropill diameter 0.8～
1.5mm；Prepared micropill is mixed with Pulvis Talci, standby；
(2) prepared by mesalazine controlled release micro pill
Preparation mass percent is 2.4% ethyl cellulose ethanol solution, and adding mass percent is 0.3% citric acid three
Ethyl ester, after stirring and dissolving, the mesalazine pastille micropill that step (1) is obtained, put bag ethyl cellulose in LBL-3 type fluid bed
Layer, controls inlet temperature 40 DEG C, air pressure≤0.5MPa, obtains mesalazine controlled release micro pill.
(3) prepared by mesalazine enteric controlled-release micropill
Preparation enteric layer coating solution is (containing mass percent 7.2% especially strange S100,0.7% triethyl citrate and 1.1%
Pulvis Talci), the mesalazine pastille micropill that step (2) is obtained, put bag enteric layer in LBL-3 type fluid bed, control air intake temperature
Spend 40 DEG C, air pressure≤0.5MPa, obtain mesalazine enteric controlled-release micropill.
Embodiment 3
| Inner core: | |
| Mesalazine | 79.5% |
| Hydroxypropyl cellulose (Klucel MF) | 8.0% |
| Controlled release coating layer: | |
| Ethyl cellulose (AqualonTM N15) | 0.9% |
| Triethyl citrate | 0.1% |
| Adhesion coatings: | |
| Sodium alginate | 3.0% |
| Enteric coat layer: | |
| Especially strange S100 | 6.7% |
| Triethyl citrate | 0.7% |
| Pulvis Talci | 1.1% |
The preparation method of above-mentioned mesalazine enteric positioning controlled-release preparation is as follows:
(1) prepared by mesalazine pastille micropill
Take mass percent to consist of the mesalazine of 79.5% and cross 80 eye mesh screens, make drug microparticles volume average particle size≤
200μm；Take mass percent again and consist of after the hydroxypropyl cellulose of 8.5% crosses 60 eye mesh screens, mix with mesalazine；Take
Above-mentioned spiece is put in fluid bed, carries out fluidized granulation with alcohol-water (70:30) solvent, controls fluidized-bed temperature 45 DEG C,
40 mesh granulate after particle drying, screening 40～60 mesh granules as parent nucleus, micropill processed in WL-300 pellet processing machine, control rotary speed
200～300rpm, inlet temperature 40 DEG C, prepare pastille micropill, control micropill diameter 0.8～1.5mm；
(2) prepared by mesalazine controlled release micro pill
Preparation percentage by weight is 1.0% ethyl cellulose ethanol solution, and mesalazine pastille step (1) obtained is micro-
Ball, puts bag ethylcellulose in LBL-3 type fluid bed, controls inlet temperature 40 DEG C, air pressure≤0.5MPa, obtains U.S. husky
Draw piperazine controlled release micro pill.
(3) prepared by mesalazine adhesion controlled release micro pill
Prepare 1% sodium alginate aqueous solution, weigh the sodium alginate aqueous solution of mass percent 2.5% by recipe quantity, will
The micropill that step (2) obtains, puts bag sodium alginate layer in LBL-3 type fluid bed, controls inlet temperature 40 DEG C, and air pressure≤
0.5MPa, obtains mesalazine and adheres to controlled release micro pill.
(4) prepared by mesalazine enteric positioning controlled-release micropill
Preparation enteric layer coating solution is (containing mass percent 6.8% especially strange S100,0.7% triethyl citrate and 1.1%
Pulvis Talci), the mesalazine pastille micropill that step (3) is obtained, put bag enteric layer in LBL-3 type fluid bed, control air intake temperature
Spend 40 DEG C, air pressure≤0.5MPa, obtain mesalazine enteric positioning controlled-release micropill.
Embodiment 4
The preparation method of above-mentioned mesalazine enteric positioning controlled-release preparation is as follows:
(1) prepared by mesalazine pastille micropill
Take mass percent to consist of the mesalazine of 70.3% and cross 80 eye mesh screens, make drug microparticles volume average particle size≤
200μm；Take mass percent again and consist of the hydroxypropyl cellulose of 5.2%, the mannitol of 5.3% and 4.7% microcrystalline Cellulose
After crossing 60 eye mesh screens, mix with mesalazine；Take above-mentioned spiece and put in fluid bed, enter with alcohol-water (60:40) solvent
Row fluidized granulation, controls fluidized-bed temperature 45 DEG C, 40 mesh granulate after particle drying, and screening 40～60 mesh granules are as parent nucleus, WL-
Micropill processed in 300 pellet processing machines, controls rotary speed 200～300rpm, inlet temperature 40 DEG C, prepares pastille micropill, controls
Micropill diameter is 0.8～1.5mm；Prepared micropill is mixed with Pulvis Talci, standby；
(2) prepared by mesalazine controlled release micro pill
Preparation percentage by weight is 2.0% ethyl cellulose ethanol solution, and mesalazine pastille step (1) obtained is micro-
Ball, puts bag ethylcellulose in LBL-3 type fluid bed, controls inlet temperature 40 DEG C, air pressure≤0.5MPa, obtains U.S. husky
Draw piperazine controlled release micro pill.
(3) prepared by mesalazine adhesion controlled release micro pill
Prepare 1% sodium alginate aqueous solution, weigh the sodium alginate aqueous solution of percentage by weight 4.2% by recipe quantity, will
The micropill that step (2) obtains, puts bag sodium alginate layer in LBL-3 type fluid bed, controls inlet temperature 40 DEG C, and air pressure≤
0.5MPa, obtains mesalazine and adheres to controlled release micro pill.
(4) prepared by mesalazine enteric positioning controlled-release micropill
Preparation enteric layer coating solution (containing percentage by weight 5.8% especially strange L100 and 0.5% triethyl citrate), will step
Suddenly the mesalazine pastille micropill that (3) obtain, puts bag enteric layer in LBL-3 type fluid bed, controls inlet temperature 40 DEG C, air pressure
Power≤0.5MPa, obtains mesalazine enteric positioning controlled-release micropill.
Embodiment 5
The preparation method of above-mentioned mesalazine preparation is as follows:
(1) prepared by mesalazine pastille micropill
Take mass percent to consist of the mesalazine of 72.5% and cross 80 eye mesh screens, make drug microparticles volume average particle size≤
200μm；Take mass percent again and consist of the crystallite fibre of the hydroxypropyl cellulose of 7.2%, the sodium alginate of 4.7% and 8.5%
After dimension element crosses 60 eye mesh screens, mix with mesalazine；Take above-mentioned spiece and put in fluid bed, fluidize with ethanol solvent
Pelletizing, control fluidized-bed temperature 45 DEG C, 40 mesh granulate after particle drying, screening 40～60 mesh granules are as parent nucleus, WL-300 system
Micropill processed in ball machine, controls rotary speed 200～300rpm, inlet temperature 40 DEG C, prepares pastille micropill, controls micropill straight
Footpath is 0.8～1.5mm, standby；
(2) prepared by mesalazine enteric coated micropill
Preparation enteric layer coating solution (containing mass percent 6.5% especially strange L100 and 0.6% triethyl citrate), will step
Suddenly the mesalazine pastille micropill that (1) obtains, puts bag enteric layer in LBL-3 type fluid bed, controls inlet temperature 40 DEG C, air pressure
Power≤0.5MPa, obtains mesalazine enteric coated micropill.
Embodiment 6
| Inner core: | |
| Mesalazine | 65.0% |
| Lactose | 16.2% |
| Hypromellose (K4M) | 8.7% |
| Carbomer 934 | 3.0% |
| Enteric coat layer: | |
| Especially strange L100 | 6.5% |
| Triethyl citrate | 0.6% |
The preparation method of above-mentioned mesalazine preparation is as follows:
(1) prepared by mesalazine pastille micropill
Take mass percent to consist of the mesalazine of 65.0% and cross 80 eye mesh screens, make drug microparticles volume average particle size
≤200μm；Take mass percent again and consist of the hypromellose of 8.7%, the carbomer 934 of 3.0% and the breast of 16.2%
After 60 eye mesh screens crossed by sugar, mix with mesalazine；Take above-mentioned spiece and put in fluid bed, carry out fluidisation system with ethanol solvent
Grain, controls fluidized-bed temperature 45 DEG C, 40 mesh granulate after particle drying, and screening 40～60 mesh granules are as parent nucleus, WL-300 pill
Micropill processed in machine, controls rotary speed 200～300rpm, inlet temperature 40 DEG C, prepares pastille micropill, controls micropill diameter
0.8～1.5mm, standby；
(2) prepared by mesalazine enteric coated micropill
Preparation enteric layer coating solution (containing mass percent 6.5% especially strange L100 and 0.6% triethyl citrate), will step
Suddenly the mesalazine pastille micropill that (1) obtains, puts bag enteric layer in LBL-3 type fluid bed, controls inlet temperature 40 DEG C, air pressure
Power≤0.5MPa, obtains mesalazine enteric coated micropill.
Embodiment 7
By preparation 3.5% carbomer 934, sodium alginate, HPMC K4M and chitosan gel rubber, 12 KM mices
(female), is randomly divided into 4 groups, vagina administration, is inverted 1 minute by mice after administration, and medicinal liquid is fully contacted with mucosa, after 24 hours
Put to death animal, observe mucosa with or without the phenomenon such as congested, red and swollen.
| Sample | Result |
| 3.5% carbomer 934 gel | Red and swollen phenomenon be can be observed |
| 3.5% sodium alginate gel | Without phenomenon congested, red and swollen |
| 3.5% HPMC K4M gel | Red and swollen phenomenon be can be observed |
| 3.5% chitosan gel rubber | Without phenomenon congested, red and swollen |
Embodiment 8
Example 1 and embodiment 2 micropill sample (respectively sample 1 and sample 2), tested by micropill gastrointestinal retentiveness rate
Method, investigates micropill gastrointestinal retentiveness rate, and result see table:
As seen from table, enteric positioning controlled-release preparation (sample 1) involved in the present invention is in the delay of the big enteral of laboratory animal
Time is far above the non-locating preparation (sample 2) without adhesion material
Embodiment 9
Example 1,3～6 micropill sample, by above-mentioned micropill acid resisting test and drug release in vitro degree assay method,
Acid resistance and the drug release in vitro degree of sample is prepared in investigation, and result see table and Fig. 1.
| Sample number into spectrum | Release amount (%, n=6) in acid |
| Embodiment 1 | 3.2±1.4 |
| Embodiment 3 | 3.6±0.9 |
| Embodiment 4 | 6.4±2.8 |
| Embodiment 5 | 4.5±3.6 |
| Embodiment 6 | 3.7±2.5 |
Write music line from release amount and drug release in vitro in sample acid, enteric positioning controlled-release system involved in the present invention
Agent is not release substantially in acid medium, can slow release 24 hours in pH7.5 medium.
Claims (8)
1. a mesalazine enteric positioning controlled-release preparation, it is characterised in that: the most successively by inner core, controlled release coating layer,
Adhere to coatings, enteric coat layer composition, containing mesalazine, hydroxypropyl cellulose and Pulvis Talci in described inner core, described
Controlled release coating layer be made up of ethyl cellulose, triethyl citrate, described adhesion coatings uses sodium alginate, described
Enteric coat layer is made up of with methylmethacrylate copolymer, triethyl citrate and Pulvis Talci methacrylic acid, each composition
Percentage by weight consist of as follows:
Mesalazine 65～86.2%；
Hydroxypropyl cellulose 2.0～11.8%；
Pulvis Talci 1.0～2.0% in inner core；
Ethyl cellulose 0.9～3.0%；
Triethyl citrate 0.1～0.5% in controlled release coating layer；
Sodium alginate 2.6～5.9%；
Methacrylic acid and methylmethacrylate copolymer 4.6～9.2%；
Triethyl citrate 0.2～1.2% in enteric coat layer；
Pulvis Talci 0.5～2.0% in enteric coat layer；
Diameter of aspirin particle≤200 μm of described mesalazine；Hydroxypropyl cellulose is in the viscosity that mass percent concentration is when 2%
It is 4000～6500 mPa s, mean molecule quantity 850000；Ethyl cellulose viscosity gluing when mass percent concentration is 5%
Degree is 6～16 mPa s, ethyl substitution value 48.0～49.5；Sodium alginate mean molecule quantity 5000～15000；Methacrylic acid
With methylmethacrylate copolymer, methacrylic acid is 1:1 or 1:2 copolymer with the mol ratio of methyl methacrylate.
A kind of mesalazine enteric positioning controlled-release preparation the most according to claim 1, it is characterised in that: the weight of each composition
Percentage ratio consists of as follows:
Mesalazine 66～76.9%；
Hydroxypropyl cellulose 6.8～11.5%；
Pulvis Talci 1.0～2.0% in inner core；
Ethyl cellulose 1.5～2.5%；
Triethyl citrate 0.1～0.5% in controlled release coating layer；
Sodium alginate 4.0～5.9%；
Methacrylic acid and methylmethacrylate copolymer 6.0～9.0%；
Triethyl citrate 0.4～0.9% in enteric coat layer；
Pulvis Talci 0.5～2.0% in enteric coat layer.
A kind of mesalazine enteric positioning controlled-release preparation the most according to claim 1, it is characterised in that: can also be containing composing
Shape agent and lubricant.
A kind of mesalazine enteric positioning controlled-release preparation the most according to claim 3, it is characterised in that: described excipient
It is any one or the two or more combination in lactose, mannitol, microcrystalline Cellulose；Described lubricant is stearic acid
Any one or two or more combination in magnesium, stearic acid, Pulvis Talci, micropowder silica gel, Polyethylene Glycol.
A kind of mesalazine enteric positioning controlled-release preparation the most according to claim 1, it is characterised in that: in described inner core
Being made up of mesalazine, lactose, hydroxypropyl cellulose and Pulvis Talci, the percentage by weight of each composition consists of as follows:
Mesalazine 66.7%；
Lactose 5.8%；
Hydroxypropyl cellulose 9.2%；
Pulvis Talci 1.6% in inner core；
Ethyl cellulose 2.4%；
Triethyl citrate 0.3% in controlled release coating layer；
Sodium alginate 5.0%；
Methacrylic acid and methylmethacrylate copolymer 7.2%；
Triethyl citrate 0.7% in enteric coat layer；
Pulvis Talci 1.1% in enteric coat layer；
Mesalazine diameter of aspirin particle≤200 μm；Hydroxypropyl cellulose mass percent concentration be viscosity when 2% be 4000～
6500, mean molecule quantity 850000；Ethyl cellulose viscosity mass percent concentration be viscosity when 5% be 6～8, ethyl takes
For degree 48.0～49.5；Sodium alginate mean molecule quantity 10000；Wherein methacrylic acid with methylmethacrylate copolymer is
The copolymer of ratio 1:2.
A kind of mesalazine enteric positioning controlled-release preparation the most according to claim 1, it is characterised in that: its dosage form is
Micropill.
7. the preparation method of a kind of mesalazine enteric positioning controlled-release preparation described in claim 1 or 5, it is characterised in that
Including following preparation process:
1) each supplementary material is weighed according to mass percent；
2) step preparing mesalazine pastille micropill；Mesalazine is crossed screen cloth, makes drug microparticles volume average particle size
≤200μm；Again by after in capsule core, 60 eye mesh screens crossed by other adjuvant, mix with mesalazine；Take said mixture and put in fluid bed,
Carrying out fluidized granulation with alcohol-water solvent, the volume ratio of second alcohol and water is 60～80:30, solvent control fluidized-bed temperature 40～
50 DEG C, 40 mesh granulate after particle drying, screening 40～60 mesh granules as parent nucleus, are put micropill processed in WL-300 pellet processing machine, are controlled
Rotary speed 200～300rpm, inlet temperature 35～45 DEG C, prepare pastille micropill, control micropill diameter 0.8～
1.5mm；By prepared micropill and the Pulvis Talci mixing in inner core, standby；
3) step preparing mesalazine controlled release micro pill；Being added by ethyl cellulose in ethanol, preparation mass percent is dense
Degree is the ethanol solution of ethyl cellulose of 1～2.5%, adds the triethyl citrate in controlled release coating layer, and stirring and dissolving will
The mesalazine pastille micropill that step (1) obtains, puts bag ethylcellulose in LBL-3 type fluid bed, controls inlet temperature 35
～45 DEG C, air pressure≤0.5MPa, obtain mesalazine controlled release micro pill；
4) step preparing mesalazine adhesion controlled release micro pill；Sodium alginate is added to the water, is configured to mass percent
Concentration is the sodium alginate aqueous solution of 0.8～1.2%, micropill step (2) obtained, and puts bag alginic acid in LBL-3 type fluid bed
Sodium layer, control inlet temperature 35～45 DEG C, air pressure≤0.5MPa, obtain mesalazine and adhere to controlled release micro pill；
5) step preparing mesalazine enteric controlled-release micropill；By methacrylic acid and methylmethacrylate copolymer,
Enteric layer coating solution is made, by step after triethyl citrate in enteric coat layer and the mixing of the Pulvis Talci in enteric coat layer
(3) the mesalazine pastille micropill obtained, puts bag enteric layer in LBL-3 type fluid bed, control inlet temperature 35～45 DEG C, air
Pressure≤0.5MPa, obtains mesalazine enteric controlled-release micropill.
The preparation method of a kind of mesalazine enteric positioning controlled-release preparation the most according to claim 7, it is characterised in that: second
In alcohol-water-soluble matchmaker, the volume ratio of second alcohol and water is 70:30.
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