CN102319218B - Drug sustained and controlled release microparticle preparation for treating intestinal diseases, and preparation method thereof - Google Patents
Drug sustained and controlled release microparticle preparation for treating intestinal diseases, and preparation method thereof Download PDFInfo
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- CN102319218B CN102319218B CN201110284698.0A CN201110284698A CN102319218B CN 102319218 B CN102319218 B CN 102319218B CN 201110284698 A CN201110284698 A CN 201110284698A CN 102319218 B CN102319218 B CN 102319218B
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- 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
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- 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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- 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
- A61K9/5078—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 with drug-free core
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- 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
- A61K9/5005—Wall or coating material
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- 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
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
- A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
- A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
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Abstract
The present invention discloses a drug sustained and controlled release microparticle preparation for treating intestinal diseases. The preparation comprises: a pill core containing the drug, wherein the pill core contains 5-aminosalicylic acid and an assistant material; an isolation layer for providing a smooth and flat surface for the microparticle and preventing the drug from penetrating into a sustained release coating layer, wherein the penetration of the drug into the sustained release coating layer can affect the release effect, the used material of the isolation layer comprises one or a plurality of materials selected from a water-soluble polymer and an anti-adhesion agent; the sustained release coating layer for slowly releasing the drug, wherein different drug release levels can be achieved through adjusting the thickness of the sustained release coating layer, the used material of the sustained release coating layer mainly adopts a sustained-release material; an enteric-coating layer, the enteric-coating layer is provided for avoiding the early release of the drug in gastric juice, reducing stimulation of the main drug to stomach, increasing the local concentration of the drug in the lesion location, the used material of the enteric-coating layer mainly adopts a polymer enteric material. The invention further discloses a preparation method for the microparticle preparation. According to the present invention, the drug and the sustained release coating material are uniformly dispersed on the surface of the pellet, such that the problem of mixing uniformity of the assistant material and the main drug can be effectively solved.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, relate in particular to a kind of slow controlled release micro pill or microparticle formulation of medicine (5-aminosalicylic acid) for the treatment of intestinal tract disease; In addition, the invention still further relates to the method for using multiple coatings technology to prepare above-mentioned slow controlled release micro pill or microparticle formulation.
Background technology
Mesalazine (being 5-aminosalicylic acid) be mainly used in clinically Crow engler (Chron ' s) treatment of sick and ulcerative colitis.But its taking dose higher (usually can use to 4g in prescription); and stomach is had to certain stimulation; and the site of pathological change for the treatment of is at colon; Orally taken product in the market adopts the method for slow release, controlled release to prepare this product more; take number of times and the stimulation to human body to reduce, improve curative effect.But most products and the related technology of invention all can not reach the object of anticipation, reason is mainly that dosage is too high and cause the adjuvant application space in preparation process lower, is difficult to reach the object of slow release and intestinal location simultaneously.
Micropill is a kind of novel polynary drug-supplying system, is subject to physiological effect little compared with conventional formulation; Gastrointestinal tract distribution area is large, can improve bioavailability and reduce local excitation; The advantages such as drug release behavior is easy to control (as conlon targeting, slow release etc.), and individual variation is little.
The common process that at present more satisfactory mesalazine (being 5-aminosalicylic acid) sustained-release pellet preparation adopts comprise principal agent mix with slow release macromolecular material and other adjuvants, granulate, extrude, round as a ball and dry etc., then the micropill obtaining is carried out to enteric coating, medicine can not discharged in advance in gastric juice, and just start release after then entering intestinal, be conducive to reduce the stimulation of principal agent to stomach and the drug level of increase lesions position (colon).
But above-mentioned technique is used in the preparation production process taking 5-aminosalicylic acid as active component and has obvious deficiency.In large-scale production process, ensure that the mix homogeneously of principal agent and adjuvant is the key factor of guaranteeing product quality.If principal agent ratio is higher in prescription, the ratio of the adjuvant that uses is lower, and these adjuvants have comprised medicine control is discharged to the material playing a crucial role, and principal agent has just become the key in production technology with the uniformity of adjuvant mixing so.In general preparation production technique, be difficult to guarantee slow release macromolecular material and mix homogeneously with principal agent and other adjuvants, thereby easily affect the releasing effect of medicine, affect the quality of medicine.
The patent No. is that the Chinese patent of CN00808889.6 also exists above-mentioned defect, and cannot reach the object that intestinal location discharges; The patent No. is the micropill system that the Chinese patent of CN200410020455.6 discloses a kind of conlon targeting, but it is obviously not enough aspect slow-release function and raising drug loading; And the disclosed content of the patent of CN200480010790.6 also can not solve the release And Spread of Solute in advance in gastric juice; The patent of CN200810232858.5 discloses a kind of segmented intestine targeted tablet technology of preparing, and mesalazine taking dose is higher, the tablet specification of producing is large (if the small pieces sheet number that client need is taken will increase greatly) generally, from Point of View of Clinical, due to the impact large (especially when by pylorus) of large specification tablet suffered gastric emptying after taking, so be easy to cause that individual variation is larger, affect the treatment.
Summary of the invention
The technical problem to be solved in the present invention is to provide a kind of medicine sustained and controlled release microparticle formulation for the treatment of intestinal tract disease and preparation method thereof, it uses multiple coatings technology, make medicine and slow release coating material be evenly dispersed in piller or globule (beads) surface, can effectively solve adjuvant mixes homogeneity problem with principal agent.
In order to solve the problems of the technologies described above, the invention provides a kind of medicine sustained and controlled release microparticle formulation for the treatment of intestinal tract disease, the main active ingredient of said preparation is 5-aminosalicylic acid, said preparation comprises:
A) containing pill core: comprise 5-aminosalicylic acid and adjuvant;
B) sealing coat: this layer of Main Function is to make granule surface be tending towards smooth rounding, and stop drug osmotic to affect releasing effect to sustained release coating layer, increase the stability of medicine, this layer main uses material to comprise one or more of water soluble polymer and suitable antitackiness agent; Described water soluble polymer refers to the macromolecular material of strongly hydrophilic, can be dissolve or swell in and in water, form aqueous solution or dispersion; Described antitackiness agent is a class material that prevents from producing adhesion in coating process;
C) sustained release coating layer: this layer of Main Function is that sustained drug is discharged lentamente, can regulate by spraying the amount of different coating solutions the thickness (generally 0.5～12% coating weightening finish level) of this layer to reach different release levels; The main slow-release material that uses of this layer; Described slow-release material refers to that some macromolecular materials are combined in preparation by different way, plays rate of release, the release time of controlling medicine and the effect that discharges position.
D) enteric coat layer: this layer of Main Function is to avoid the release in advance of principal agent in gastric juice, reduces the stimulation of principal agent to stomach, improves the local concentration of medicine at lesions position; The main macromolecule enteric material that uses of this layer.Described macromolecule enteric material is the class pH dependent form macromolecular material in slow-release material, and in gastric juice, (pH < 5) do not dissolve, and (in intestinal juice) can dissolve fast under higher pH condition.
Describedly adopt celphere drug layering or extrude round as a ball technique and make containing pill core; Described adjuvant comprises one or more of following adjuvant: polyvidone PVP, hypromellose HPMC, sodium carboxymethyl cellulose CMC-Na, methylcellulose MC, hydroxypropyl cellulose HPC, Hydroxypropyl methyl cellulose phtalate HPMCP, microcrystalline Cellulose, starch, dextrin, lactose, magnesium stearate, water.
Preferably, described containing the preparation of pill core employing celphere drug layering, described adjuvant comprises one or more of following adjuvant: sucrose, microcrystalline Cellulose, starch, polyvidone PVP, hydroxypropyl cellulose HPC, Hydroxypropyl methyl cellulose phtalate HPMCP, hypromellose HPMC, Pulvis Talci.
Describedly adopt and extrude the preparation of round as a ball technique containing pill core, described adjuvant comprises forming agent or diluent, binding agent and lubricant, is preferably microcrystalline Cellulose, polyvidone PVP and magnesium stearate.Described is 50～99% containing 5-aminosalicylic acid content in pill core, is preferably 70～85%, and microcrystalline cellulose cellulose content is 5%～40%, be preferably 10～22%, polyvidone PVP content is 1～15%, is preferably 4～9%, magnesium stearate content is 0～8%, is preferably 0.1～1.5%.
The use material of described sealing coat comprises following one or more: Pulvis Talci, titanium dioxide, Kaolin, polyvidone PVP, hypromellose HPMC, hydroxypropyl cellulose HPC, PVAC polyvinylalcohol, Hydroxypropyl methyl cellulose phtalate HPMCP, Polyethylene Glycol PEG.
The use material of described sustained release coating layer comprises following one or several: cellulose derivative, acrylic resin analog derivative, and other available slow-release materials.Described cellulose derivative refers to the product after hydroxyl and chemical reagent generation esterification or the etherification reaction in cellulose macromolecule; Described acrylic resin analog derivative refers to the general name of methacrylic acid copolymer and methacrylate copolymer.
The macromolecule enteric material that described enteric coat layer is used comprises following one or several: acrylic resin base polymer, Lac, CAP CAP and other available enteric materials and selectable antitackiness agent, plasticizer, solvent.Described acrylic resin base polymer, also referred to as acrylic resin analog derivative, refers to the general name of methacrylic acid copolymer and methacrylate copolymer.Described antitackiness agent is the class material preventing in preparation art for coating process in the raw adhesion of bag pill; Described plasticizer refers to as improving the flexible compounds of coating membrane; Described Lac is the one of enteric-coating material, is Lacciferidae insecticide lac insect secreted colloid on branch.
Preferably, the adjuvant that described sealing coat uses is Pulvis Talci and polyvidone PVP, and its part by weight is 1: 2～5: 1, and preferably 3: 1, coating level reached weightening finish 0～15%, preferably 2～5%; The adjuvant that described sustained release coating layer mainly uses is ethyl cellulose and Pulvis Talci, and solid weight ratio is 2: 1～10: 1, and preferably 5: 1～7: 1, coating level reached weightening finish 0.5～12%, preferably 1～4%; The adjuvant that described enteric coat layer is mainly used is acrylic resin, triethyl citrate, Pulvis Talci, ethanol, acetone, water, and preferably adjuvant is acrylic resin, and coating level reaches weightening finish 5～32%, preferably 11～28%.
In addition, the present invention also provides a kind of preparation method of medicine sustained and controlled release microparticle formulation for the treatment of intestinal tract disease, comprises the steps:
(1) preparation is containing pill core;
(2) each layer of soluble in water the mixing of adjuvant made to sealing coat coating solution, sustained release coating layer coating solution, enteric coat layer coating solution;
(3) what step (1) is made inserts coating equipment in sugar production line containing pill core, carries out successively sealing coat coating, sustained release coating layer coating and enteric coat layer coating.
In step (1), described preparation adopts celphere drug layering or extrudes round as a ball technique containing pill core; Described celphere drug layering is specially: get containing the each component of pill core material and stir, the suspension of preparing solid content 10-20% is for subsequent use; Pack celphere into coating equipment in sugar production line preheating, bed temperature pumps into the suspension of medicine during higher than 35 DEG C until finish, and with a small amount of water rinse container and pipeline, is dried, and obtains containing pill core; Describedly extrude round as a ball technique and be specially: get containing the each component of pill core material and fully mix, then add appropriate water to prepare soft material, by further the soft material obtaining extrusion granulator, then use the round as a ball wet ball core that can obtain suitable size of spheronizator, this ball core is further dried and sieves, and obtains containing pill core.
Step (3) is specially: prepared by step (1) inserts in fluid bed containing pill core, make bed temperature be greater than 35 DEG C with hot-air preheating, start to spray sealing coat coating solution and carry out sealing coat coating, approximately 1.5～3.5g/min of coating solution flow velocity, pressure 0.7～2.5kg/m
2, bed temperature remains on 25～35 DEG C, after coating finishes, continues to blow hot-air dry 20min, continues to spray slow release layer coating solution and carries out slow release layer coating, approximately 1.5～3.5g/min of coating solution flow velocity, pressure 0.7～2.5kg/m
2, bed temperature remains on 25～35 DEG C, and after coating completes, the dry 20min of continuation, then sprays enteric layer coating solution and carries out enteric layer coating, approximately 1.5～3.5g/min of coating solution flow velocity, pressure 0.7～2.5kg/m
2, bed temperature remains on 25～35 DEG C, then continues to be dried to product moisture lower than 3%, to obtain final product.
The present invention compared with prior art, there is following beneficial effect: a kind of medicine sustained and controlled release microparticle formulation for the treatment of intestinal tract disease of the present invention and preparation method thereof, principal agent and functional adjuvant in formulation products can be distributed at piller or globule (beads) surface uniform effectively, and medicine is discharged to delay prosecutor formula, the homogeneity that can more guarantee any constituent content in product, is mainly reflected in:
1. by using packaging technique or extruding round as a ball technique, can prepare content uniformly containing pill core;
2. use packaging technique containing pill wicking surface parcel one deck sealing coat, to ensure that the medicine in ball core can not be penetrated into sustained release coating layer, and make piller surface be tending towards smooth rounding;
3. use packaging technique, by repeatedly play the macromolecular solution of slow releasing function in prepared piller surface sprinkling, can make these materials can be wrapped in equably prepared piller surface;
4. the various compositions that play enteric effect are sprayed on piller, to ensure that every kind of composition can be wrapped in piller surface equably;
5. in the high drug load situation that does not increase adjuvant usage ratio, prepared medicine can reach intestinal location and slow release object simultaneously;
6. avoid the in advance release of medicine in gastric juice, reduce the stimulation of medicine to stomach on the one hand, increase on the other hand the unstability that medicine causes due to gastric acid;
7. with the mode administration of piller, be subject to physiologic factor impact compared with little and can enter very soon intestinal; Enter after intestinal, each piller can, separately as a slow release of release unit, reach permanent mechanism, reduces medicining times, compliance when raising patient takes medicine;
8. compared with common mix and blend method, can more guarantee the homogeneity of any constituent content and the stability of release in product;
9. the method disclosed in the present and technique, can also be used for the medicine (as intestinal local disease, some acid nonfast medicines etc.) of other similar therapeutic purposes.
Brief description of the drawings
Fig. 1 is micropill external release profiles result schematic diagram under the gastrointestinal tract condition of different pH of simulation in embodiment 6.
Detailed description of the invention
The following examples further illustrate the present invention, but the present invention is not limited to following listed embodiment:
Embodiment 1
Prescription containing pill core:
1 mesalazine 750g
2 microcrystalline Cellulose 195g
Celphere
3 polyvidone 45g
4 water are appropriate
Ball core preparation method: get the above pill core prescription component 1,3,4 that contains and stir, the suspension of preparing solid content 10-20% is for subsequent use; Pack component 2 celphere into coating equipment in sugar production line preheating, bed temperature pumps into the suspension of medicine during higher than 35 DEG C until finish, with a small amount of water rinse container and pipeline, dry, obtains qualified rapid release and contains pill core.
Coating prescription:
1 polyvidone 20.0g
2 Pulvis Talci 7.5g
3 water 270g
4 ethyl cellulose 20.0g
5 Pulvis Talci 2.5g
6 water 175g
7 methacrylic acid 215.0g
And metering system
Acid methyl ester 1: 1
Copolymer
8 95% ethanol 860g
The preparation of coating solution: first polyvidone and Pulvis Talci are dispersed in to (component 1,2,3 in coating prescription) in aqueous solution, it is for subsequent use that mistake 60 mesh sieves are made sealing coat coating solution.Ethyl cellulose and Pulvis Talci (component 4,5 in prescription) are dispersed in aqueous solution (component 6 in coating prescription), mix and stir, it is for subsequent use that mistake 60 mesh sieves are made sustained release coating liquid; Component 7 is dispersed in component 8, and crossing 60 mesh sieves, to make enteric layer coating solution for subsequent use.
Art for coating: the pastille rapid release ball core of preparation is inserted to fluid bed or other coating equipment in sugar production lines, make bed temperature be greater than 35 DEG C with hot-air preheating, start to spray sealing coat coating solution bag sealing coat, the about 1.5g/min of coating solution flow velocity, pressure 0.7kg/m
2(bed temperature remains on 25 DEG C), after coating finishes, continues to blow hot-air dry 20min, proceeds sustained release coating and (sprays slow release layer coating solution, the about 1.5g/min of coating solution flow velocity, pressure 0.7kg/m
2(bed temperature remains on 25 DEG C)), after coating completes, then the dry 20min of continuation carries out enteric coating (sprinkling enteric layer coating solution, the about 1.5g/min of coating solution flow velocity, pressure 0.7kg/m
2(bed temperature remains on 25 DEG C)), then continue to be dried to product moisture lower than 3%, to obtain final product.
Embodiment 2
Prescription containing pill core:
1 mesalazine 750g
2 microcrystalline Cellulose 195g
3 polyvidone 45g
4 magnesium stearate 10g
5 water are appropriate
Ball core preparation method: get above each component and fully mix, can use dissimilar mixing apparatus or high shear wet granulator, then add appropriate water to prepare soft material.By further the soft material obtaining extrusion granulator, then use the round as a ball wet ball core that can obtain suitable size of spheronizator, this ball core is further dried and sieves, and obtains qualified pastille rapid release ball core.
Coating prescription:
1 polyvidone 25.0g
2 Pulvis Talci 8.0g
3 water 270g
4 ethyl cellulose 16.9g
5 Pulvis Talci 4.1g
6 water 185.0g
7 methacrylic acid 150g
With acrylic acid second
1: 1 copolymer of ester
8 Fructus Citri Limoniae triethylenetetraminehexaacetic acid 30g
Ester
9 Pulvis Talci 50g
10 water 1200g
The preparation of coating solution: first polyvidone and Pulvis Talci are dispersed in to (component 1,2,3 in coating prescription) in aqueous solution, it is for subsequent use that mistake 60 mesh sieves are made sealing coat coating solution.Component 4,5 in prescription is dispersed in the aqueous solution of prescription component 6, mixes and be uniformly dispersed, it is for subsequent use that mistake 60 mesh sieves are made slow release layer coating solution; Component 7,8,9 is dispersed in component 10 water, and crossing 60 mesh sieves, to make enteric coating liquid for subsequent use.
Art for coating: the pastille rapid release ball core of preparation is inserted to fluid bed or other coating equipment in sugar production lines, make bed temperature be greater than 35 DEG C with hot-air preheating, start to spray sealing coat coating solution bag sealing coat, the about 3.5g/min of coating solution flow velocity, pressure 2.5kg/m
2, (bed temperature remains on 35 DEG C), after coating finishes, continues to blow hot-air dry 20min, proceeds sustained release coating and (sprays slow release layer coating solution, the about 3.5g/min of coating solution flow velocity, pressure 2.5kg/m
2, (bed temperature remains on 35 DEG C)), after coating completes, then the dry 20min of continuation carries out enteric coating (sprinkling enteric layer coating solution, the about 3.5g/min of coating solution flow velocity, pressure 2.5kg/m
2, (bed temperature remains on 35 DEG C)), then continue to be dried to product moisture lower than 3%, to obtain final product.
Embodiment 3
Prescription containing pill core:
1 mesalazine 950g
2 microcrystalline Cellulose 40g
3 hydroxypropyl first fiber 5g
Element
4 magnesium stearate 5g
5 water are appropriate
Ball core preparation method: get above each component and fully mix, can use dissimilar mixing apparatus or high shear wet granulator, then add appropriate water to prepare soft material.By further the soft material obtaining extrusion granulator, then use the round as a ball wet ball core that can obtain suitable size of spheronizator, this ball core is further dried and sieves, and obtains qualified pastille rapid release ball core.
Coating prescription:
1 polyvidone 15.0g
2 Pulvis Talci 7.5g
3 water 210g
4 ethyl cellulose 15.9g
5 Pulvis Talci 2.1g
6 water 165g
7 methacrylic acid 250g
And metering system
Acid methyl ester is total at 1: 2
Polymers
8 Fructus Citri Limoniae triethylenetetraminehexaacetic acid 50g
Ester
9 acetone 1000g
The preparation of coating solution: first polyvidone and Pulvis Talci are dispersed in to (component 1,2,3 in coating prescription) in aqueous solution, it is for subsequent use that mistake 60 mesh sieves are made sealing coat coating solution.Component 4,5 in coating prescription is dispersed in aqueous solution (component 6 in coating prescription), mixes and stir, it is for subsequent use that mistake 60 mesh sieves are made slow release layer coating solution; Component 7 and component 8 are dispersed in component 9 and fully dispersion, and it is for subsequent use that mistake 60 mesh sieves are made enteric coating liquid.
Art for coating: the pastille rapid release ball core of preparation is inserted to fluid bed or other coating equipment in sugar production lines, make bed temperature be greater than 35 DEG C with hot-air preheating, start to wrap sealing coat, the about 2g/min of coating solution flow velocity, pressure 1kg/m
2, (bed temperature remains on 30 DEG C), after coating finishes, continues to blow hot-air dry 20min, proceeds sustained release coating and (sprays slow release layer coating solution, the about 2g/min of coating solution flow velocity, pressure 1kg/m
2, (bed temperature remains on 30 DEG C)), after coating completes, then the dry 20min of continuation carries out enteric coating (sprinkling enteric layer coating solution, the about 2g/min of coating solution flow velocity, pressure 1kg/m
2, (bed temperature remains on 30 DEG C)), then continue to be dried to product moisture lower than 3%, to obtain final product.
Embodiment 4
Prescription containing pill core:
1 mesalazine 550g
2 microcrystalline Cellulose 355g
3 polyvidone 45g
4 magnesium stearate 50g
5 water are appropriate
Ball core preparation method: get above each component and fully mix, can use dissimilar mixing apparatus or high shear wet granulator, then add appropriate water to prepare soft material.By further the soft material obtaining extrusion granulator, then use the round as a ball wet ball core that can obtain suitable size of spheronizator, this ball core is further dried and sieves, and obtains qualified pastille rapid release ball core.
Coating prescription:
1 hydroxypropyl first fiber 22.5g
Element
2 Pulvis Talci 6.5g
3 water 270g
4 ethyl cellulose 15.9g
5 Pulvis Talci 3.8g
6 water 166.45g
7 methacrylic acid 125g
With acrylic acid second
1: 1 copolymer of ester
8 1mol/L NH
3 70g
9 Fructus Citri Limoniae triethylenetetraminehexaacetic acid 62.5g
Ester
10 water 932.5g
The preparation of coating solution: first hypromellose and Pulvis Talci are dispersed in to (component 1,2,3 in coating prescription) in aqueous solution, it is for subsequent use that mistake 60 mesh sieves are made sealing coat coating solution; Coating prescription component 4,5 in prescription is dispersed in the aqueous solution of prescription component 6, mixes and stir, it is for subsequent use that mistake 60 mesh sieves are made slow release layer coating solution; Component 7 is dispersed in 2/3 component 10, then adds component 8 and stir 1h to form above acrylic resin mixed liquor; Then component 9 is mixed homogeneously and then added acrylic resin mixed liquor to continue to stir 1h with remaining 1/3 component 10, suspendible coating solution is crossed to 60 mesh sieves, and to make enteric coating liquid for subsequent use.
Art for coating: the pastille rapid release ball core of preparation is inserted to fluid bed or other coating equipment in sugar production lines, make bed temperature be greater than 35 DEG C with hot-air preheating, start to wrap sealing coat, the about 3g/min of coating solution flow velocity, pressure 2kg/m
2, (bed temperature remains on 30 DEG C), after coating finishes, continues to blow hot-air dry 20min, proceeds sustained release coating and (sprays slow release layer coating solution, the about 3g/min of coating solution flow velocity, pressure 2kg/m
2, (bed temperature remains on 30 DEG C)), after coating completes, then the dry 20min of continuation carries out enteric coating (sprinkling enteric layer coating solution, the about 3g/min of coating solution flow velocity, pressure 2kg/m
2, (bed temperature remains on 30 DEG C)), then continue to be dried to product moisture lower than 3%, to obtain final product.
Embodiment 5
Prescription containing pill core:
1 mesalazine 900g
2 microcrystalline Cellulose 90g
3 polyvidone 5g
4 magnesium stearate 5g
5 water are appropriate
Ball core preparation method: get above each component and fully mix, can use dissimilar mixing apparatus or high shear wet granulator, then add appropriate water to prepare soft material.By further the soft material obtaining extrusion granulator, then use the round as a ball wet ball core that can obtain suitable size of spheronizator, this ball core is further dried and sieves, and obtains qualified pastille rapid release ball core.
Coating prescription:
1 polyvidone 15.0g
2 Pulvis Talci 7.5g
3 water 210g
4 ethyl acrylate, 105.0g
Methacrylic acid
Methyl ester and methyl
Acrylic acid chlorination
Trimethylamine groups second
Ester 1: 2: 0.1
Copolymer
5 Fructus Citri Limoniae triethylenetetraminehexaacetic acid 15.0g
Ester
6 Pulvis Talci 10.0g
7 water 585g
8 methacrylic acid 250g
And metering system
Acid methyl ester is total at 1: 2
Polymers
9 Fructus Citri Limoniae triethylenetetraminehexaacetic acid 50g
Ester
10 acetone 1000g
The preparation of coating solution: first polyvidone and Pulvis Talci are dispersed in to (component 1,2,3 in coating prescription) in aqueous solution, it is for subsequent use that mistake 60 mesh sieves are made sealing coat coating solution.Component 4,5,6 in coating prescription is dispersed in aqueous solution (component 7 in coating prescription), mixes and stir, it is for subsequent use that mistake 60 mesh sieves are made slow release layer coating solution; Component 8 and component 9 are dispersed in component 10 and fully dispersion, and it is for subsequent use that mistake 60 mesh sieves are made enteric coating liquid.
Art for coating: the pastille rapid release ball core of preparation is inserted to fluid bed or other coating equipment in sugar production lines, make bed temperature be greater than 35 DEG C with hot-air preheating, start to spray sealing coat coating solution, the about 3g/min of coating solution flow velocity, pressure 2kg/m
2, (bed temperature remains on 30 DEG C), after coating finishes, continues to blow hot-air dry 20min, proceeds sustained release coating and (sprays slow release layer coating solution, the about 3g/min of coating solution flow velocity, pressure 2kg/m
2, (bed temperature remains on 30 DEG C)), after coating completes, then the dry 20min of continuation carries out enteric coating (sprinkling enteric layer coating solution, the about 3g/min of coating solution flow velocity, pressure 2kg/m
2, (bed temperature remains on 30 DEG C)), then continue to be dried to product moisture lower than 3%, to obtain final product.
Embodiment 6
The micropill of embodiment 2 is carried out to the release experiment of the pH variation of the each section of Gl tract, release conditions: rotating speed 100rpm, 900mL dissolution medium, temperature is 37 ± 0.5 DEG C.0～2h dissolution medium is the HCl solution of pH1.0, and the 3rd hour dissolution medium is replaced by the phosphate buffer of pH6.8, and result is as shown in table 1 and Fig. 1:
Table 1 and Fig. 1 are that the micropill of embodiment 2 discharges result under the gastrointestinal tract condition of different pH of simulation, and SD can illustrate the advantage of the prepared micropill medicine-releasing system of this method aspect enteric and release stability:
The prepared product of three crowdes of embodiment 2 of table 1. is in different time and pH condition cumulative release
Experimental design in above embodiment requires to discharge lower than 5% for piller 2h in gastric juice, and in intestinal juice, 0.5h discharges 10-30%, and 1h discharges 30-50%, and 2h discharges 60-80%, in 7 hours, discharges and is not less than 80%.Generally, in preparation technical process, in order to prove the stability of technique, can use identical technique to produce some batches (i.e. three batches of products in table 1), between the product batches of producing, difference less (this experiment represents with standard deviation SD), illustrates that technique is more stable.As can be seen from Table 1, the poor SD of each point release standard is all less than 3, illustrates that this technique is highly stable, also just explanation from the side, and it is very uniform that principal agent and adjuvant mix.
Claims (15)
1. treat a medicine sustained and controlled release microparticle formulation for intestinal tract disease, the main active ingredient of said preparation is 5-aminosalicylic acid, it is characterized in that, said preparation comprises:
A) containing pill core: comprise 5-aminosalicylic acid and adjuvant;
B) sealing coat: this layer of Main Function is to make granule surface be tending towards smooth rounding, and stop drug osmotic to affect releasing effect to sustained release coating layer, increase the stability of medicine, this layer of main use material comprises one or more of water soluble polymer and antitackiness agent;
C) sustained release coating layer: this layer of Main Function is that sustained drug is discharged lentamente, can be by regulating the thickness of this layer to reach different release levels; The main slow-release material that uses of this layer;
D) enteric coat layer: this layer of Main Function is to avoid the release in advance of principal agent in gastric juice, reduces the stimulation of principal agent to stomach, improves the local concentration of medicine at lesions position; The main macromolecule enteric material that uses of this layer, described macromolecule enteric material is the class pH dependent form macromolecular material in slow-release material; Described macromolecule enteric material is methacrylic acid and ethyl acrylate 1:1 copolymer.
2. the medicine sustained and controlled release microparticle formulation for the treatment of intestinal tract disease as claimed in claim 1, is characterized in that, describedly adopts celphere drug layering or extrudes round as a ball technique and make containing pill core; Described adjuvant comprises one or more of following adjuvant: polyvidone PVP, hypromellose HPMC, sodium carboxymethyl cellulose CMC-Na, methylcellulose MC, hydroxypropyl cellulose HPC, Hydroxypropyl methyl cellulose phtalate HPMCP, microcrystalline Cellulose, starch, dextrin, lactose, magnesium stearate, water.
3. the medicine sustained and controlled release microparticle formulation for the treatment of intestinal tract disease as claimed in claim 2, it is characterized in that, described containing the preparation of pill core employing celphere drug layering, described adjuvant comprises one or more of following adjuvant: sucrose, microcrystalline Cellulose, starch, polyvidone PVP, hydroxypropyl cellulose HPC, Hydroxypropyl methyl cellulose phtalate HPMCP, hypromellose HPMC, Pulvis Talci.
4. the medicine sustained and controlled release microparticle formulation for the treatment of intestinal tract disease as claimed in claim 2, is characterized in that, describedly adopts and extrudes the preparation of round as a ball technique containing pill core, and described adjuvant comprises forming agent or diluent, binding agent and lubricant.
5. the medicine sustained and controlled release microparticle formulation for the treatment of intestinal tract disease as claimed in claim 4, is characterized in that, described adjuvant comprises microcrystalline Cellulose, polyvidone PVP and magnesium stearate.
6. the medicine sustained and controlled release microparticle formulation for the treatment of intestinal tract disease as claimed in claim 1, it is characterized in that, the use material of described sealing coat comprises following one or more: Pulvis Talci, titanium dioxide, Kaolin, polyvidone PVP, hypromellose HPMC, hydroxypropyl cellulose HPC, PVAC polyvinylalcohol, Hydroxypropyl methyl cellulose phtalate HPMCP, Polyethylene Glycol PEG.
7. the medicine sustained and controlled release microparticle formulation for the treatment of intestinal tract disease as claimed in claim 1, it is characterized in that, the use material of described sustained release coating layer comprises following one or several: cellulose derivative, acrylic resin analog derivative, and other available slow-release materials.
8. the medicine sustained and controlled release microparticle formulation for the treatment of intestinal tract disease as claimed in claim 1, it is characterized in that, the adjuvant that described sealing coat uses is Pulvis Talci and polyvidone PVP, the adjuvant that described sustained release coating layer mainly uses is ethyl cellulose and Pulvis Talci, and the adjuvant that described enteric coat layer is mainly used is methacrylic acid and ethyl acrylate 1:1 copolymer, triethyl citrate, Pulvis Talci, ethanol, acetone, water.
9. the medicine sustained and controlled release microparticle formulation for the treatment of intestinal tract disease as claimed in claim 5, it is characterized in that, described is 50～99% containing 5-aminosalicylic acid content in pill core, and microcrystalline cellulose cellulose content is 5%～40%, polyvidone PVP content is 1～15%, and magnesium stearate content is 0～8%.
10. the medicine sustained and controlled release microparticle formulation for the treatment of intestinal tract disease as claimed in claim 9, is characterized in that, described is 70～85% containing 5-aminosalicylic acid content in pill core; Described microcrystalline cellulose cellulose content is 10～22%; Polyvidone PVP content is 4～9%; Magnesium stearate content is 0.1～1.5%.
The medicine sustained and controlled release microparticle formulation of 11. treatment intestinal tract diseases as claimed in claim 8, is characterized in that, adjuvant polyvidone PVP and Pulvis Talci that described sealing coat uses, and part by weight is 1:2～5:1; Coating level reaches weightening finish 0～15%; Adjuvant ethyl cellulose and Pulvis Talci that described sustained release coating layer uses, solid weight ratio is 2:1～10:1, coating level reaches weightening finish 0.5～12%; The adjuvant that described enteric coat layer is used is methacrylic acid and ethyl acrylate 1:1 copolymer, and coating level reaches weightening finish 5～32%.
The medicine sustained and controlled release microparticle formulation of 12. treatment intestinal tract diseases as claimed in claim 11, is characterized in that, adjuvant polyvidone PVP and Pulvis Talci that described sealing coat uses, and ratio is 3:1; Coating level reaches weightening finish 2～5%; Adjuvant ethyl cellulose and Pulvis Talci that described sustained release coating layer uses, solid weight ratio is 5:1～7:1, coating level reaches weightening finish 1～4%; The adjuvant that described enteric coat layer is used is methacrylic acid and ethyl acrylate 1:1 copolymer, and coating level reaches weightening finish 11～28%.
The preparation method of the medicine sustained and controlled release microparticle formulation of 13. 1 kinds for the treatment of intestinal tract diseases as described in claim 1-12 any one, is characterized in that, comprises the steps:
(1) preparation is containing pill core;
(2) each layer of soluble in water the mixing of adjuvant made to sealing coat coating solution, sustained release coating layer coating solution, enteric coat layer coating solution;
(3) what step (1) is made inserts coating equipment in sugar production line containing pill core, carries out successively sealing coat coating, sustained release coating layer coating and enteric coat layer coating.
The preparation method of the medicine sustained and controlled release microparticle formulation of 14. treatment intestinal tract diseases as claimed in claim 13, is characterized in that, in step (1), described preparation adopts celphere drug layering or extrudes round as a ball technique containing pill core; Described celphere drug layering is specially: get containing the each component of pill core material and stir, the suspension of preparing solid content 10-20% is for subsequent use; Pack celphere into coating equipment in sugar production line preheating, bed temperature pumps into the suspension of medicine during higher than 35 DEG C until finish, and with a small amount of water rinse container and pipeline, is dried, and obtains containing pill core; Describedly extrude round as a ball technique and be specially: get containing the each component of pill core material and fully mix, then add appropriate water to prepare soft material, by further the soft material obtaining extrusion granulator, then use the round as a ball wet ball core that can obtain suitable size of spheronizator, this ball core is further dried and sieves, and obtains containing pill core.
The preparation method of the medicine sustained and controlled release microparticle formulation of 15. treatment intestinal tract diseases as claimed in claim 13, it is characterized in that, step (3) is specially: prepared by step (1) inserts in fluid bed containing pill core, make bed temperature be greater than 35 DEG C with hot-air preheating, start to spray sealing coat coating solution and carry out sealing coat coating, coating solution flow velocity is 1.5～3.5g/min, and pressure is 0.7～2.5kg/m
2, bed temperature remains on 25～35 DEG C, after coating finishes, continues to blow hot-air dry 20min, continues to spray slow release layer coating solution and carries out slow release layer coating, and coating solution flow velocity is 1.5～3.5g/min, and pressure is 0.7～2.5kg/m
2, bed temperature remains on 25～35 DEG C, and after coating completes, the dry 20min of continuation, then sprays enteric layer coating solution and carries out enteric layer coating, and coating solution flow velocity is 1.5～3.5g/min, and pressure is 0.7～2.5kg/m
2, bed temperature remains on 25～35 DEG C, then continues to be dried to product moisture lower than 3%, to obtain final product.
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| CN201110284698.0A CN102319218B (en) | 2011-09-22 | 2011-09-22 | Drug sustained and controlled release microparticle preparation for treating intestinal diseases, and preparation method thereof |
| PCT/CN2012/071756 WO2013040873A1 (en) | 2011-09-22 | 2012-02-29 | Sustained and controlled release of micro-granule formulation for treating intestinal disease and preparation method thereof |
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| CN201110284698.0A CN102319218B (en) | 2011-09-22 | 2011-09-22 | Drug sustained and controlled release microparticle preparation for treating intestinal diseases, and preparation method thereof |
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| JOP20200144A1 (en) | 2012-04-30 | 2017-06-16 | Tillotts Pharma Ag | A delayed release drug formulation |
| EP3062776A1 (en) * | 2013-10-29 | 2016-09-07 | Tillotts Pharma AG | A delayed release drug formulation |
| SG11201606439VA (en) | 2014-02-07 | 2016-09-29 | Dong Wha Pharm Co Ltd | Anticancer adjuvant composition containing rip3 expression promoter as active ingredient, method for screening for anticancer adjuvant enhancing sensitivity of anticancer drug by promoting rip3 expression, and method for monitoring sensitivity of anticancer drug |
| WO2015193788A1 (en) * | 2014-06-16 | 2015-12-23 | Valpharma International S.P.A. | Formulation for oral administration containing mesalazine |
| CN104257669A (en) * | 2014-09-25 | 2015-01-07 | 合肥平光制药有限公司 | Oral administration composition for delivering salicylic acid medicines to intestinal tract |
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