CN102762198A - Multi-unit compositions - Google Patents
Multi-unit compositions Download PDFInfo
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- CN102762198A CN102762198A CN2011800100428A CN201180010042A CN102762198A CN 102762198 A CN102762198 A CN 102762198A CN 2011800100428 A CN2011800100428 A CN 2011800100428A CN 201180010042 A CN201180010042 A CN 201180010042A CN 102762198 A CN102762198 A CN 102762198A
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- Prior art keywords
- coating
- ball core
- agent
- spherolite
- neutral
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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
- A61K9/48—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
- 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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
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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
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
- A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
Abstract
Disclosed herein a compressed tablet composition comprising (a) coated multiple units, containing at least one active pharmaceutical ingredient, (b) at least one compressibility enhancing agent comprising neutral spheres, (c) at least one cohesiveness imparting agent comprising binder(s). Such a composition provides solution to chipping, cracking and leaking problems associated with compression of coated multiple units (pellets or beads).
Description
Technical field
The present invention relates to a kind of multiple-unit Tableted compositions.
Background technology
Multiple-unit dosage form (multiple unit dosage forms) is many granule medicaments transmission system, comprises that a plurality of pillers, granule, bead, microsphere, micro tablet or other can be by the medicines that comprises cluster of grains (agglomerations of particles) of putting into capsule or being pressed into tablet.The multiple-unit dosage form is compared with traditional only first dosage form and is demonstrated numerous significant advantages.These advantages comprise the diversity that reduces gastric emptying; Weaken dependency to nutriture; Reduce the high risk of local drug concentration in the gastrointestinal tract; Reduce individual in and the diversity between individuality, the zero-time of control drug release and the active component of acid labile is passed to intestinal lower end (lower end), and the release of control highly-water-soluble active component.
Yet multiad compound also has many shortcomings.Their manufacturing is very complicated, and the prescription of the manufacturing of multiple unit pharmaceutical preparation compositions is great challenge especially.
The coating of formula material is known at pharmaceutical field.Coating can be realized a lot of functions.It can change the mode that medicine discharges from dosage form, promptly prolongs or postpone to discharge active pharmaceutical ingredient (API), covers the taste of API, and prevents from the adverse effect in the accessory drugs of environmental condition and common processing.Become in the process of tablet at the multiple-unit coating, coating receives the required pressure of conversion and when being damaged, the basic goal of coating has just fallen through.When the substrate of coating during in higher relatively particle size range, this phenomenon is very obvious.In addition, in coated substrate is processed the process of tabletting, other various challenges are arranged.The tabletting that has been noted that multiple-unit or the piller of coating possibly cause explosion and the fragment in the material (tablet) by compression, and this is owing to lack cohesiveness and held back air in the aggregation closely in the compressed mixture.These surperficial cracks not only can cause indecency outward appearance but also can cause high percent defective, and so unacceptable finished product low-yield.The outward appearance that product is not beautiful also can cause poor patient acceptable.In addition, TGA and other international medical science and health supervision department, for example USFDA and MHRA implement strict registration requirement to these products.
Prior art references has been described pharmaceutical composition and has been used to tackle the problem that the coating mechanical damage that is caused by pressure causes coating function and uniformity of dosage units loss.
The multiple unit pharmaceutical preparation dosage form (MUPS) that comprises proton pump inhibitor or its alkali salt has been described in EP0723437.The production of MUPS is the mixed of pressing 60:40 through with full of enteric coated granules (enteric coated beads) and tablet accessory drugs, then with the mixture tabletting.Disclosed compositions has adopted the plasticizer of high concentration to support with anti-mechanical damage to coating with outer coatings polymeric layer (overcoating layer of polymers) in coatings in this list of references.
EP0548356 has taught a kind of MUPS of Orally disintegrating by supposition, includes the microcrystal and the micropill of the active pharmaceutical ingredient of taste masking coating.Said compositions comprises disintegrating agent and sweller or dissolvable agents further.
Transfer the US7314640 of Andrx, disclose the particulate MUPS of the sustained release coating that comprises metroprolol succinate, super-disintegrant, buffer agent, filler and lubricant.
EP1837016 discloses medicinal multiad compound, and it comprises the active component unit and the shielded granule that comprises microcrystalline Cellulose and Polyethylene Glycol of coating.Said compositions display improve resistant function to mechanical damage.
WO2010/018593 discloses anti-gastric acid benzimidazole multiple unit pharmaceutical preparation compositions, and said composition comprises, includes the enteric-coated pellets of the buffer agent of benzimidazole compound and macrogol form.
WO2008/014175 discloses the wet granulation of the coated granule of active pharmaceutical ingredient, and it uses the microcrystalline Cellulose of adhesive and silication, and follows tabletting after adding disintegrating agent and lubricant.Such compositions provides better content uniformity.
Goal of the invention
Main purpose of the present invention provides a kind of multiple-unit compositions for tableting, and it has slick surface and does not have problems such as crack, fragment, calotte (capping) and aperture.
Another purpose of compositions of the present invention is to improve the yield rate that comprises the multiunit tabletting of coating.
Another purpose of compositions of the present invention is to prevent or make the damage of the multiunit coating behind the tabletting reduce to minimum.
Summary of the invention
The present invention relates to the multiunit Tableted compositions of a kind of functional coatings, it comprises at least a active pharmaceutical ingredient and at least a function coating.Compositions of the present invention provides tabletting a kind of and coating multiple-unit (piller or granule) relevant crack, fragment and run-down way to solve the problem.In addition, tablet composition of the present invention is graceful in outward appearance, and this has increased the acceptability of patient to dosage form.
On the one hand; The invention provides a kind of Tableted compositions; Comprise that (a) comprises the coating multiple-unit of at least a active constituents of medicine and at least a function coating, (b) at least a compressibility reinforcing agent that comprises neutral spherolite, (c) at least a viscosity imparting agent that comprises adhesive; And (d) alternatively, other tabletting adjuvants.
Preferably, comprise the compressibility reinforcing agent of neutral spherolite, the viscosity imparting agent that comprises adhesive and other optional tabletting adjuvants and carry out the outer mixing of grain.
The multiple-unit of this compositions is selected from grain, piller, granule, crystal grain and microgranule.Preferred multiple-unit is piller or granule.Use or do not use adhesive, active component is mixed in perhaps covers (layered) in the granule on granule or piller layer.
The multiple-unit of this compositions also comprises at least a function coating.For compositions of the present invention; The function coating is selected from: be intended to prolong drug and continue or sustained release coating from what the ball core discharged, delayed release coating, taste masking coating, give the coating of active pharmaceutical ingredient stability following or that cover or change multiunit structure so that the further coating of processing.Stability protection can be resisted other adjuvants in environmental factors or the compositions.The multiple-unit of this compositions is the combination of above-mentioned coating also.
The weight that the coating multiple-unit constitutes accounts for total sheet heavily from 20% to 60%, and preferably from 30% to 50%.For the purposes of the present invention, the concentration of all components (percent is represented) is based on total sheet weight.
The ratio of compressibility reinforcing agent and viscosity imparting agent is useful for compositions of the present invention.Preferably, the ratio of compressibility reinforcing agent and viscosity imparting agent is from 8:1 to 2:1, and more preferably, ratio is from 6:1 to 4:1.
This compressibility reinforcing agent comprises neutral spherolite.Used neutral spherolite can be selected from microcrystalline Cellulose type
cane sugar type (celphere) and corn starch type in the tablet composition of the present invention, or their any combination.The neutral spherolite of being made up of silicon dioxide, dicalcium phosphate, calcium stearate, magnesium stearate, glass, polypropylene, polyethylene, ethyl cellulose, hydroxyethyl-cellulose or the like also is considered for compositions of the present invention.
The weight that neutral spherolite constitutes accounts for total sheet heavily from 2% to 40%, and preferably from 5% to 30%, more preferably from 5% to 20%.
Extremely important composition viscosity imparting agent comprises adhesive in the Tableted compositions of the present invention.The scope that these adhesive are selected from is (1) natural polymer, for example starch, pregelatinized Starch, gelatin, arabic gum, alginic acid, sodium alginate, xanthan gum, tracasol, karaya, Tragacanth, Fructus anacardii glue, card Europe glue, aluminium-magnesium silicate and pod marrow Lignum Sappan glue; (2) sugar, for example sucrose, glucose (dextrose), sorbitol, mannitol and maltodextrin; (3) synthetic polymer; For example for example Eudragit NE30 D, Eudragit RS 30D, Eudragit EPO, Eudragit LI 00 of kollidon (polyvidone), XLPE ketopyrrolidine, vinyl-pyrrolidone vinyl acetate co-polymer
hypromellose (hydroxypropyl emthylcellulose), hyprolose, methylcellulose, sodium carboxymethyl cellulose, Polyethylene Glycol, ethyl cellulose, polyvinyl alcohol, microcrystalline Cellulose and polymethacrylates (Eudragit), or their combination.Preferably adhesive is the polyvidone of brand name for
that obtains from BASF AG.Kollidon can generally be dryness or moist adhesive.Preferably, the weight that adhesive constitutes accounts for total sheet heavily from 0.5% to 15%, and more preferably from 2% to 10%.
Preferably, the ratio of neutral spherolite and adhesive is from 2:1 to 8:1, more preferably from 4:1 to 6:1.
The active pharmaceutical ingredient that the present invention considers is for producing any active component of the therapeutic response of requirement at human or animal's health when with the mode administration recommended.The classification of active pharmaceutical ingredient is (a) proton pump inhibitor, for example esomeprazole, omeprazole, lansoprazole, pantoprazole, rabeprazole or the like; (b) beta-blocker, for example atenolol, bisoprolol, esmolol, Propranolol and metoprolol or the like; (c) antidepressants, for example duloxetine, venlafaxine, tolterodine, olanzapine or the like; (d) antiallergic agent, for example cetirizine, loratadine, Desloratadine, fexofenadine and montelukast or the like; (e) NSAID, for example indomethacin, diclofenac sodium or diclofenac potassium or the like; (f) bring down a fever and analgesic, for example acetaminophen, aspirin, mefenamic acid, tramadol or the like; (g) antimigraine, for example sumatriptan, rizatriptan, clonazepam, Zolmitriptan, Frova, naratriptan, eletriptan, almotriptan or the like; (h) antuepileptic, for example carbamazepine, lamotrigine, levetiracetam or the like; (i) Bendectin, for example domperidone, metoclopramide and ondansetron or the like.Other active constituents of medicine scope possibly comprise; But be not limited only to; Antacid, antibiotics, antibacterial, spasmolytic, antianxiety drugs, lipid lowerers, hormones, enzyme, cough medicine, diarrhea, antiviral drugs, cathartic, anoretics, hydryllin, anti-asthmatic, mucus regulator, antidiuretic, anti-flatulence agent, antuepileptic, biological product, spasmolytic, tranquilizer, psychosis (risperidone, Quetiapine or the like), Focalin, antihypertensive, tranquilizer, decongestant, and their combination.Any combination of above-mentioned active pharmaceutical ingredient also can be used for compositions of the present invention.
Other various tabletting adjuvants comprise filler, buffer agent, disintegrating agent, flavoring agent, sweetener, pigment, antitack agent, fluidizer, lubricant or the like.
Although producing the method for optimizing of compositions of the present invention is direct compression, the production method that other are conventional, for example tabletting after wet granulation or the non-slurry pelletizing also belongs to category of the present invention.
The specific embodiment
Definition
Coating multiple-unit (Coated multiple units): term as used herein " coating multiple-unit " refers to the multiple inertia ball core that encapsulates with sealing coating, lamination medicine-feeding, sub-coating and/or function coating (not necessarily with such order).The multiunit component of coating constitutes component in the granule.For the purposes of the present invention, the coating multiple-unit also is called piller or granule.
Multiple unit pharmaceutical preparation (Multiple unit tablets): term used herein " multiple unit pharmaceutical preparation " refer to through with the coating multiple-unit with neutral spherolite (neutral spheres), adhesive and other tabletting adjuvants such as filler, disintegrating agent, buffer agent, lubricant and antitack agent compress or tabletting forms tablet.
Grain outer component (Extragranular constituents): neutral spherolite used herein, adhesive and other tabletting adjuvants such as filler, disintegrating agent, buffer agent, lubricant and antitack agent are the outer component of grain.The outer component of grain promotes coating multiple-unit tabletting or is compressed in the tablet.
Yield rate (yield): term used herein " yield rate " be tablet quantity that practice examining is qualified divided by predetermined in batches in the theoretical quantity of tablet, the percentage ratio that calculates numeral.
Calotte (capping): term used herein " calotte " refers to; Top or the following part of Swertia Tablet; Partly or wholly flatly separate, and separating as a medicated cap from the tablet machine demoulding or subsequent treatment from the tablet main body.
Crack (cracking): term used herein " crack " refers to the upper and lower central surface at tablet, and/or little, the trickle crackle of finding at the sidewall of tablet.
Run-down (leaking): term used herein " run-down " refers to be observed the coating multiple-unit and from tabletting, exposes.
The coating multiple-unit
Coating multiple-unit among the present invention is preferably through the medicine-feeding of lamination on inertia ball core (drug layering) preparation.Inertia ball core among the present invention can be water-soluble, water-swellable with water-fast.Celphere (Non-pareil seed, NPS) or the sucrose ball be the example of water-soluble type inertia ball core.NPS is the spheroidal particle of white, and the sucrose that contains 62-92% is starch with remaining.NPS can (JRS Pharma USA) buys acquisition, and different sieve sizes is arranged from U.S. JRS drugmaker.The suitable example of water-swellable ball core is the microcrystalline Cellulose ball-type; Can buy acquisition from FMC Corp., brand name is glass piller and thick silicon piller for
typical water-insoluble inertia ball core.Inertia ball core must have enough density and intensity to withstand pressure and the tension force in the coating process.Preferably; Be used for the present invention tablet inertia ball core for
preferably, the granularity of inertia ball core is selected from following sieve size: 40-60 mesh sieve (250-425 μ m), 40-50 mesh sieve (420-300 μ m), 35-40 mesh sieve (425-500 μ m), 30-35 mesh sieve (500-600 μ m), 25-30 mesh sieve (600-710 μ m), 20-25 mesh sieve (710-850 μ m), 18-20 mesh sieve (850-1000 μ m), 16-18 mesh sieve (1000-1180 μ m), 14-16 mesh sieve (1000-1400 μ m).
In a preferred embodiment, the diameter range of inertia ball core is about from 250 to 600 μ m, preferably from 300 to 500 μ m, more preferably 300 to 420 μ m.Perhaps, can adopt the combination of above-mentioned sieve size.Preferably, inertia ball core constitutes the multiunit weight of coating from about 5% to 30%, more preferably, accounts for the multiunit weight of coating from about 10% to 25%.
Inertia ball core is basically by active pharmaceutical ingredient and optional adhesive, and dispersion liquid/suspension/solution water or non-water that other optional pharmacy acceptable auxiliary such as filler, stabilizing agent, surfactant, antitack agent or the like are formed is carried out coating.
The active pharmaceutical ingredient that the present invention considers does, when with the mode administration recommended, can produce any composition of the therapeutic response that requires at human or animal's health.The classification of active pharmaceutical ingredient is (a) proton pump inhibitor, for example esomeprazole, omeprazole, lansoprazole, pantoprazole, rabeprazole or the like; (b) beta-blocker, for example atenolol, bisoprolol, esmolol, Propranolol and metoprolol or the like; (c) antidepressants, for example duloxetine, venlafaxine, tolterodine, olanzapine or the like; (d) antiallergic agent, for example cetirizine, loratadine, Desloratadine, fexofenadine and montelukast or the like; (e) NSAID, for example indomethacin, diclofenac sodium or diclofenac potassium or the like; (f) bring down a fever and analgesic, for example acetaminophen, aspirin, mefenamic acid, tramadol or the like; (g) antimigraine, for example sumatriptan, rizatriptan, clonazepam, Zolmitriptan, Frova, naratriptan, eletriptan, almotriptan or the like; (h) antuepileptic, for example carbamazepine, lamotrigine, levetiracetam or the like.The classification of other active constituents of medicine can comprise; But be not limited only to; Antacid, antibiotics, antibacterial, Bendectin, spasmolytic, antianxiety drugs, lipid lowerers, hormones, enzyme, antitussive, diarrhea, antiviral drugs, cathartic, anorexigenic, hydryllin, anti-asthmatic, mucus regulator, antidiuretic, anti-flatulence agent, antuepileptic, antimigraine, biological product, spasmolytic, tranquilizer, psychosis (risperidone, Quetiapine or the like), Focalin (antihyperactives), antihypertensive, tranquilizer, decongestant, and their combination.Any combination of above-mentioned active pharmaceutical ingredient also can be used for compositions of the present invention.Preferably, active pharmaceutical ingredient constitutes the multiunit weight of coating from about about 5% to 60%.
In one embodiment, most preferred active agents is esomeprazole, lansoprazole, omeprazole, olanzapine and metoprolol.
The suitable example of preferred intragranular adhesive is polyvinylpyrrolidone, hydroxyethyl-cellulose, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, polyacrylate and ethyl cellulose.Most preferably among the embodiment, adhesive is hydroxypropyl cellulose (HPC) in the present invention.HPC; Use as adhesive; Can buy acquisition from U.S. Aqualon company, brand name is
EF and EXF.Adhesive constitutes the multiunit weight of coating and is up to 15%, preferably is up to 5%.
Suitable antitack agent (anti-tacking agent) comprises, but is not limited only to Pulvis Talci, silicon dioxide and magnesium stearate.Antitack agent constitutes the multiunit weight of coating and preferably is up to 1%.
Through any routine techniques as known in the art, such as pan coating method, drum-type pelletize (roto-granulation) or fluid bed (fluidized bed) coating, (drug layer) is applied on the inertia ball core with the medicine layer.In the operation of such coating, medicine disperses or dissolves or is suspended in a kind of organic or aqueous solvent, wherein also can comprise aforesaid adjuvant.The dicyandiamide solution that is used to process the lamination medicine-feeding can be water water or non-.Suitable non-aqueous solution can be pure, for example methanol, ethanol, isopropyl alcohol (IPA); Water alcohol, for example water-isopropyl alcohol; Organic solvent, the for example combination of acetone, dichloromethane or aforesaid these solvents.In a preferred embodiment,, adopt pure water in the fluid bed processor that is equipped with the Wurster instrument, to carry out the lamination medicine-feeding then as aqueous solvent.
The lamination medicine-feeding constitutes the multiunit weight of coating from 5% to 50%.
One separates coating can be applied to API and comprise between layer and the function coatings or at API and comprise between layer and the inertia ball core.Separate coating and comprise water miscible and/or water-insoluble polymer, antitack agent with, alternatively, alkali or sour agent and filler.Water-soluble polymer is an example with hydroxypropyl cellulose or hydroxypropyl emthylcellulose and polyethylene glycols (Polyethylene Glycol is PEG-6000 for example), and preferred water-insoluble polymer is an ethyl cellulose.Filler is an example with sucrose, lactose, mannitol, xylitol and sorbitol.Antitack agent can be Pulvis Talci, silicon dioxide colloid or glyceryl monostearate.The various alkaline agents of expection are sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide and magnesium oxide.The organic acid example is citric acid, fumaric acid and tartaric acid.Separating coating can apply with fluid bed processor.
Coating multiple-unit in this compositions also comprises at least a function coating.Function coating in the compositions of the present invention is selected from: be intended to slow release or prolongation release coating that prolong drug discharges from the ball core; Delayed release coating, the taste masking coating gives the coating of active pharmaceutical ingredient stability following or that cover, and changes multiunit structure so that the coating of further processing.Stability protection can be resisted other adjuvants in environmental factors or the compositions.Coating multiple-unit in this compositions also can have the combination of above-mentioned coating.
Multiunit coating mainly comprise polymer, plasticizer, antistatic additive, opacifiers, antitack agent, stabilizing agent, surfactant, coloring agent, pigment, antifoam and, alternatively, alkali or sour agent or PH regulator.
The type that is used for the polymer of coating depends on the function of conceivable coating.For example; For enteric coating or anti-gastric solubleness coating (gastro-resistant coating); Polymer is selected from HPMCP, hydroxypropyl methylcellulose acetate succinate, cellulose acetate succinate, CAP, acetic acid hydroxypropyl methylcellulose succinate, acetic acid-1; 2; 4-benzenetricarboxylic acid cellulose (cellulose acetate trimellitate), phthalic acid starch acetate (starch acetate phthalate), polyvinyl acetate phthalic acid ester, acrylic acid and/or methacrylic acid and be selected from following monomeric copolymer: methyl methacrylate, EMA, ethyl acrylate, butyl methacrylate, N-Hexyl methacrylate, decyl-octyl methacrylate, lauryl methacrylate, phenyl methacrylate, acrylic acid methyl ester., isopropylacrylic acid ester, isobutyl group acrylic ester or octadecyl acrylate, for example EUDRAGI
TM-L is such as can be from German Rohm pharmaceutically acceptable polymer company (Rohm Pharma Polymers, the L100-55, L30D55, L100, S100, the L12.5 that Germany) obtain.Also can use the combination of aforesaid polymer.
For slow release or prolong to discharge or controlled release coat, polymer is selected from: cellulose ethers such as methylcellulose, hydroxypropyl emthylcellulose, ethyl cellulose, gather oxireme (PEO), is can obtain under the Polyox in brand name; Polyvinylpyrrolidone (PVP) and vinyl pyrrolidone/vinyl acetate copolymer (copolyvidone), aforesaid methacrylate copolymer is EUDRAGIT in brand name
TMUnder can obtain, such as Eudragit RL 100, Eudragit RS 100, Eudragit RL 30D/RS 30D, Eudragit NE 30D.Also can use the combination of aforesaid polymer.
For the taste masking coating, the combination of polymers that EP997143 B1 and US7695735 describe all is considered.Yet preferred taste masking polymer is the combination of ethyl cellulose and hydroxypropyl emthylcellulose; Or polybutyl methacrylate, (2-dimethylaminoethyl) methacrylate and methyl methacrylate are EUDRAGIT with the combination of the ratio of 1:2:1 in brand name
TM(Eudragit-E, Eudragit E-100 can obtain under E-12.5).These polymer do not dissolve but swelling in saliva, and only are dissolved in the sour environment of stomach.
For the coating that stability is provided, this polymer or material are selected from hyprolose, hydroxypropyl emthylcellulose, hydroxyethyl-cellulose, sodium carboxymethyl cellulose, methylcellulose, polyvinylpyrrolidone (PVP) and vinylpyrrolidone/vinyl acetate copolymer (copolyvidone), mannitol, polyethylene glycols (Polyethylene Glycol), sorbitol, sucrose, ethyl cellulose and polymethacrylates.These coatings can contain alkaline agent, for example magnesium oxide, magnesium hydroxide, sodium hydroxide, sodium carbonate and sodium bicarbonate extraly.Similarly, coating also can comprise organic acid such as citric acid and tartaric acid.
Based on the multiunit gross weight of coating, preferably the amount that exists of coating accounts for approximately about from 10% to 90% by weight.More preferably, based on the multiunit gross weight of coating, the amount that coating exists accounts for approximately about from 25% to 70% by weight.Coating preferably is applied to multiple-unit through the packaging technique of routine, fluid bed for example, use polymer aqueous solution or appropriate organic solvent solution or with the latex suspension of these polymers.
The combination of difference in functionality coating can be applied to multiple-unit.
The coating component also comprises plasticizer except polymer, this plasticizer be selected from citrate (ATEC, acetyl tributyl-, tributyl-, triethyl group-citrate); Glycerol and glyceride (diacetine, glyceryl triacetate, acetylation monoglycceride (acetylated monoglyceride), Oleum Ricini); Phthalic acid ester (dibutyl-, diamyl-, diethyl-, dimethyl-, dipropyl-phthalic acid ester, two-(2-methoxyl group-or 2-ethoxyethyl)-phthalic acid ester); Ethyl phthalate, butyl phthalyl glycolic butyl ester (butylphthalylethyl glycolate) and glycolic butyl ester; Alcohols (Polyethylene Glycol of propylene glycol, different chain length); Adipate ester (diethylene adipate, two-(the 2-methoxyl group-or the 2-ethoxyethyl)-adipate ester); Benzophenone; Diethyl-with dibutyl sebacate, di-n-butyl succinate, dibutyl tartrate; Diethylene glycol dipropionate; Ethylene acetate ,-dibutyrate ,-dipropionate; Tributyl phosphate, tributyrin; Polyoxyethylene sorbitan monooleate dehydration (polysorbate esters, for example polysorbate 80); Arlacel-80.Also can use the combination of plasticizer.
Normally, be that every kind of coating polymer is optimized the amount of plasticizer and usually based on the gross weight of coating polymer, be expressed as by weight about about 1% to 50%, preferably 2% to 20%.
The antistatic additive that uses in the coating is selected from colloid silicon, Pulvis Talci and magnesium stearate.The concentration of the antistatic additive that uses based on the weight of coating polymer, is up to 7% by weight, preferably is up to 5%.
The surfactant that uses in the coating can be sodium laurylsulfate, polyoxyethylene sorbitan monoleate and polysorbate 20.Based on the weight of coating polymer, preferably the scope of surfactant is up to 5% by weight.
Preferably, multiunit coating is in the fluid bed processor that is equipped with the Wurster instrument, to carry out.Yet other packaging technique also can be used for multiunit coating.
For compositions of the present invention, prepare the coating multiple-unit through extruding granulator, quick stirring granulating machine or fluid bed processor.Yet multiunit preferable methods is lamination medicine-feeding and the coating that adopts the fluid bed processor of Wurster instrument.
Heavy based on total sheet, the multiunit formation of coating by weight from 20% to 60%.Preferably, heavy based on total sheet, multiunit formation of coating by weight from 30% to 50%.
The multiunit tabletting of coating
Tableted compositions of the present invention comprises that (a) comprises the coating multiple-unit of at least a active constituents of medicine and at least a function coating; (b) at least a compressibility reinforcing agent that comprises neutral spherolite; (c) at least a caking property imparting agent that comprises adhesive; And (d) alternatively, other tabletting adjuvants.
The outer component of grain
Neutral spherolite (neutral spheres)
The compressibility reinforcing agent comprises neutral spherolite.The neutral spherolite that uses in the tablet composition of the present invention can be selected from; Microcrystalline Cellulose (MCC) type spherolite
cane sugar type (celphere) spherolite and corn starch type spherolite, or their any combination.The neutral spherolite of being processed by silicon dioxide, dicalcium phosphate, calcium stearate, magnesium stearate, glass, polypropylene, polyethylene, polystyrene, ethyl cellulose, hydroxyethyl-cellulose or the like also is considered for compositions of the present invention.Alternatively; The preparation of neutral spherolite can through with sugar or sugar alcohols or their chemically modified derivative for example lactose, maltose alcohol, sucrose, starch, microcrystalline Cellulose, mannitol or the like and suitable granulating agent such as hydroxypropyl emthylcellulose, hydroxypropyl cellulose, methylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, Radix Acaciae senegalis, water or the like granulate, and obtain the granule of suitable shape and size.
For tablet composition of the present invention, the feature description of preferred neutral spherolite such as following table:
For compositions of the present invention, the selection more preferably of neutral spherolite is the cane sugar type ball.Neutral spherolite constitute account for by weight total sheet heavy from 2% to 40%, preferably from 5% to 30%.More preferably, heavy based on total sheet, by weight from 5% to 20%.For compositions of the present invention, the outer neutral spherolite of the blended grain of tabletting is very crucial.The preferred granularity of neutral spherolite is 280 μ m to 450 μ m; And be shaped as sphere.
The viscosity imparting agent
Extremely important composition viscosity imparting agent comprises adhesive in the Tableted compositions of the present invention.The scope that these adhesive are selected from is (1) natural polymer, for example starch, pregelatinized Starch, gelatin, arabic gum, alginic acid, sodium alginate, xanthan gum, tracasol, karaya, Tragacanth, Fructus anacardii glue, card Europe glue (Anacardium occidentale gum), aluminium-magnesium silicate and pod marrow Lignum Sappan glue (detarium gum); (2) sugar, for example sucrose, glucose (dextrose), sorbitol, mannitol, chitosan and maltodextrin; (3) synthetic polymer; For example for example Eudragit NE30 D, Eudragit RS 30D, Eudragit EPO, Eudragit LI00 of kollidon (polyvidone), XLPE ketopyrrolidine, vinyl arsenic pyrrolidone vinyl acetate co-polymer
hydroxypropyl emthylcellulose (hypromellose), hydroxypropyl cellulose, methylcellulose, sodium carboxymethyl cellulose, Polyethylene Glycol, ethyl cellulose, polyvinyl alcohol, microcrystalline Cellulose and polymethacrylates (Eudragit), or their any combination.Preferably adhesive is the polyvidone of brand name for
that obtains from BASF AG.Kollidon has multiple use to can be dryness or moist adhesive.Preferably, heavy based on total sheet, the weight from 0.5% to 15% that adhesive constitutes, more preferably from 2.0% to 10%.
The combination of neutral spherolite and adhesive is useful for compositions of the present invention.As if the ratio of neutral spherolite and adhesive also play a role in compositions of the present invention.Preferably, the ratio of neutral spherolite and adhesive is 2:1 to 8:1, and more preferably ratio is 4:1 to 6:1.
The quantity of other tabletting adjuvants and character thereof interact and help the multiunit successful tabletting of coating (compression).
Other various tabletting adjuvants comprise filler, surfactant, buffer agent, disintegrating agent, flavoring agent, sweetener, coloring agent, antitack agent, fluidizer, lubricant or the like.
Filler is selected from microcrystalline Cellulose, cellulose, mannitol, sorbitol, sucrose, dicalcium phosphate, lactose, DCL, starch, modified starch, pregelatinized Starch or their any combination or their any common processing combination.Filler also can carry out modification with the characteristic of giving direct compression and good flowability.Available direct compressible filler brand name is Avicel PHI02, Pearlitol DC 300 or the like.
Heavy based on total sheet, filler constitutes by weight from 30% to 60%, and preferably from 40% to 50%.
Buffer agent in the compositions of the present invention is precipitated silica (precipitated silica), microcrystalline Cellulose, Polyethylene Glycol (Macrogol) and mannitol particles.The weight that buffer agent constitutes accounts for total sheet heavily from 0.5% to 5%.
The disintegrating agent that uses in the compositions of the present invention is modified starch (like pregelatinized Starch), microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose and carboxymethylstach sodium, polyvinylpolypyrrolidone (crospolyvinylpyrrolidone; Be
XL in brand name, XL 10 is available), low substituted hydroxypropyl cellulose (L-HPC).The weight that disintegrating agent constitutes accounts for total sheet heavily from 0.5% to 10%.
The weight that flavoring agent or sweetener constitute accounts for total sheet and heavily is no more than 1%.
Coloring agent, ferrum oxide for example, the weight of formation accounts for total sheet and heavily is no more than 1%.
The non-limitative example of lubricant comprises calcium stearate, magnesium stearate and sodium stearyl fumarate or their combination.The weight that lubricant constitutes accounts for total sheet and heavily is up to 5%.
The suitable example of antitack agent comprises colloid silicon, Pulvis Talci and magnesium stearate.The weight that antitack agent constitutes accounts for total sheet and heavily is up to 5%.
The suitable example of fluidizer comprises silicon dioxide colloid, starch and Pulvis Talci or their combination.The weight that fluidizer constitutes accounts for total sheet and heavily is up to 5%.
As if neutral spherolite and adhesive exist cooperative effect.The combination of neutral spherolite and adhesive makes tablet not have crack, fragment and calotte, causes the yield rate of tabletting to significantly improve.
Alternatively, tabletting of the present invention can carry out film coating to improve its aesthetic property.Thin film coating material and its usage are that the technical staff knows.
Tablet composition of the present invention can prepare through dry method or wet granulation, and then carries out tabletting at suitable tabletting machine with suitable mold.
Preferred this method for compositions of manufacturing is a direct compression.Direct compression is a kind of routine, the general and good technology of cost efficiency.This technology comprises that the coating multiple-unit mixes with neutral spherolite, adhesive and other tabletting adjuvants, then in the tabletting machine with this mixture tabletting.
In preferred embodiment, the preparation process of tablet composition of the present invention comprises step therein:
(a) with active component coating inertia ball core; (b) will be used one or more stratum disjunctum coatings by the ball core of active component coating, (c) with the function coating ball core coating of coating stratum disjunctum, and said ball core is dry; (d) with the ball core of function coating and neutral spherolite, adhesive and alternatively filler mix; (e) alternatively, buffer agent is mixed respectively with disintegrating agent, lubricant and antitack agent, (f) alternatively the product of step (d) and step (e) is mixed; (g) last, with step (d) or mixture tabletting on tablet machine of (f) obtaining.
In another embodiment, the preparation process of tablet composition of the present invention comprises step:
(a) on inertia ball core, carry out sealed packet clothing layer coating, and then sealing coated pill core is carried out coating with active component, (b) will be by the ball core of active component coating with one or more stratum disjunctum coatings; (c) with the function coating ball core coating of coating stratum disjunctum; And said ball core is dry, (d) with the ball core of function coating and neutral spherolite, adhesive and alternatively filler mix, (e) alternatively; Buffer agent is mixed respectively with disintegrating agent and antitack agent; (f) product of step (d) and step (e) is mixed, (g) last, with step (d) or mixture tabletting on tablet machine of (f) obtaining.
Following example has proved that tablet composition of the present invention avoided all tabletting and coating defectives, has improved yield rate widely and has increased aesthetic feeling.These examples are only used exemplary illustration, and should not constitute the restriction of the scope of the invention.
The multiad compound of enteric (Gastro-resistant) coating of instance 1-esomeprazole magnesium
Table 1
Manufacture process:
1. the weight of inspection all the components is correct.
2. hyprolose is scattered in the pure water.
3. polyvinylpolypyrrolidone is joined in the dispersion liquid of step 2.
4. through stirring amorphous esomeprazole magnesium is joined in the dispersion liquid of step 3.
5. the inertia ball core of the specified quantity fluid bed processor of packing into is used the dispersion liquid coating of step 4 then.
6. the ball core (piller) of dry lamination medicine-feeding also sieves through the sieve aperture of suitable size.
7. the sugar with confection is scattered in the pure water of q.s.
8. through stirring magnesium oxide and Pulvis Talci are joined in the dispersion liquid of step 7.
9. with pack into fluid bed processor and of the ball core (piller) of lamination medicine-feeding with the dispersion liquid coating of the inferior coating I of step 8.
10. the ball core (piller) of inferior coating is carried out sieve aperture dry and through suitable size.
11. Polyethylene Glycol (Macrogol 6000) is scattered in the pure water of q.s through stirring.
12. with pack into fluid bed processor and of the ball core (piller) of step 10 Central Asia coating with the inferior coating II dispersion liquid coating of step 11.
13. the sieve aperture ball core (piller) of step 12 Central Asia coating is dry and through suitable size.
14. polysorbate 80 and glyceryl monostearate are dissolved in the pure water of q.s.
15. Polyethylene Glycol (Macrogol 400) is dissolved in the pure water of q.s, the solution that obtains is joined in the solution of step 14 through stirring.
16. EUDRAGIT S100 (Eudragit L 30 D) is joined in Eudragit L 30 dispersion liquids through #100 mesh sieve hole and with the dispersion liquid of step 15.
17. with pack into fluid bed processor and of the piller of the inferior coating of step 13 with the dispersion liquid coating of step 16.
18. it is the enteric-coated pellets that obtains is dry also through suitable sieve aperture.
19. Polyethylene Glycol (Macrogol 400) is scattered in the mixture of pure water and acetone through stirring.
20. under stirring condition, HPMCP (55) is joined in the dispersion liquid of above-mentioned steps 19.
21. with pack into fluid bed processor and of the enteric-coated pellets of step 18 with the dispersion liquid coating of step 20.
22. it is the enteric-coated pellets of step 21 is dry also through suitable sieve aperture.
Embodiment 2-Lansoprazole intestine coating multiple-unit
Table 2
| Composition | Content (mg) |
| The lamination medicine-feeding | |
| Inertia ball core | 60.0 |
| Lansoprazole | 30.0 |
| Magnesium carbonate | 22.50 |
| Icing Sugar and starch | 25.00 |
| Low substituted hyprolose (L-HPC) | 10.00 |
| Corn starch | 10.00 |
| Polyvinylpolypyrrolidone | 5.00 |
| Red ferric oxide | 0.06 |
| Hyprolose | 4.00 |
| Pure water | In right amount |
| The sealing coating | |
| The piller of lamination medicine-feeding | 166.56 |
| Icing Sugar and starch | 13.10 |
| L-HPC | 9.88 |
| Corn starch | 8.69 |
| Hyprolose | 1.60 |
| Pure water | In right amount |
| Enteric coating-I | |
| The piller of sealing coating | 199.83 |
| EUDRAGIT S100 (Eudragit L-30D55) | 45.00 |
| Glyceryl monostearate | 2.25 |
| Polysorbate 80 | 0.90 |
| Polyethylene glycol 6000 | 6.75 |
| Pure water | In right amount |
| Enteric coating-II |
| The piller of enteric coating | 254.73 |
| Hydroxypropyl methyl cellulose phtalate-55 (HPMCP-55) | 23.15 |
| PEG400 | 2.32 |
| Acetone | In right amount |
| Pure water | In right amount |
| Gross weight | 280.20 |
Manufacture process:
1. the weight of inspection all the components is correct.
2. hyprolose and ferrum oxide are scattered in the pure water.
3. magnesium carbonate, Icing Sugar and starch, low substituted hyprolose, corn starch and polyvinylpolypyrrolidone are joined in the dispersion liquid of step 2.
4. through continuing to stir lansoprazole is joined in the above-mentioned solution.
5. celphere (Celphere) fluid bed processor of packing into is used the dispersion liquid coating of step 4 then.
6. the ball core (piller) of lamination medicine-feeding is carried out sieve aperture dry and through suitable size.
7. hyprolose and ferrum oxide are scattered in the pure water.
8. Icing Sugar and starch, low substituted hyprolose and corn starch are joined in the dispersion liquid of step 7.
9. with pack into fluid bed processor and of the ball core (piller) of lamination medicine-feeding with the dispersion liquid coating of step 8.
10. the ball core (piller) of inferior coating is carried out sieve aperture dry and through suitable size.
11. polysorbate 80 is scattered in the pure water then Polyethylene Glycol and glyceryl monostearate is scattered in the said dispersion liquid.
12. the EUDRAGIT S100 (Eudragit L-30 D55) of requirement is passed through #100 purpose sieve aperture.
13. the content of step 11 is joined in the content of step 12.
Fluid bed processor pack into also with the dispersion liquid coating of step 13 14. will seal the piller of coating, then that the piller of this enteric coating is dry.
15. PEG400 is scattered in the mixture of pure water and acetone
16. HPMCP-55 is joined in the dispersion liquid of step 15 through continuing to stir.
17. with pack into fluid bed processor and of the enteric-coated pellets of step 14 with the dispersion liquid coating of step 16.
18. it is the enteric-coated pellets of step 17 is dry also through suitable sieve aperture.
Embodiment 3-metroprolol succinate sustained-release coating multiple-unit
Table 3
| Composition | Content (mg) |
| The sealing coating | |
| Inertia ball core | 73.00 |
| Ethylcellulose dispersion | 9.16 |
| Pulvis Talci | 1.02 |
| Magnesium stearate | 1.02 |
| Dichloromethane | In right amount |
| Isopropyl alcohol | In right amount |
| The lamination medicine-feeding | |
| Metroprolol succinate | 190.0 |
| Pure water | In right amount |
| Sustained release coating | |
| Ethyl cellulose | 32.11 |
| Hydroxypropyl emthylcellulose | 8.02 |
| Pulvis Talci | 4.01 |
| Magnesium stearate | 4.01 |
| Dichloromethane | In right amount |
| Isopropyl alcohol | In right amount |
| Coating again | |
| Polyethylene Glycol | 77.68 |
| Dichloromethane | In right amount |
| Isopropyl alcohol | In right amount |
| Gross weight | 400.03 |
Manufacture process:
(1) through stirring ethyl cellulose is dissolved in the mixed liquor of isopropyl alcohol and dichloromethane.
(2) magnesium stearate and Pulvis Talci are joined in the dispersion liquid of step 1.
(3) with pack into fluid bed processor and carry out coating of inertia ball core with the sealed packet clothing dispersion liquid of step 2.
(4) the inertia ball core of step 3 sealing coating is dry also through 30 purpose mesh screens.
(5) through stirring metroprolol succinate is dissolved in pure water.
Pack into fluid bed processor and of the inertia ball core that (6) will seal coating with the dispersion liquid coating of step 5.
(7) the inertia ball core (piller) of drug coating is dry also through 20 purpose mesh screens.
(8) through stirring ethyl cellulose and hydroxypropyl emthylcellulose are scattered in the mixed liquor of isopropyl alcohol and dichloromethane.
(9) Pulvis Talci and magnesium stearate are joined in the dispersion liquid of step 8.
(10) with pack into fluid bed processor and of the ball core (piller) of step 7 drug coating with the dispersion liquid coating of step 9.
(11) the ball core (piller) of step 10 sustained release coating is dry also through 20 purpose mesh screens.
(12) polyethylene glycol 6000 is dissolved in the mixed liquor of isopropyl alcohol and dichloromethane.
(13) with pack into fluid bed processor and of the piller of step 11 with the solution coating of step 12.
(14) piller of step 13 is the dry and mesh screen through suitable size.
The compositions (MUPS) of instance 4-tabletting multiple unit pharmaceutical preparation
Table 4
There is the problem of mentioning in+expression
There is not the problem of mentioning in-expression
Find clearly that from above data compositions of the present invention has significantly improved yield rate.
The manufacture process of MUPS (processing-) (instance 4.1 and 4.2)
1, ferrum oxide and microcrystalline Cellulose mixing are sieved through the #36 order then.
2, the enteric piller of instance 1 step 22 is through the #16 mesh sieve.
3, the raw material with above step 1, step 2 mixed 10 minutes with neutral spherolite (NPS).
4, Polyethylene Glycol (Macrogol 6000), polyvinylpolypyrrolidone (Polyplasdone XL), polyvinylpyrrolidone (Povidone K-90), pregelatinized Starch and silica gel are sieved through the #36 order.
5, with the raw material of step 3 with from the raw materials mix of step 4 10 minutes.
6, will use suitable mould tabletting at tablet machine from the lubriation material that step 5 obtains.
Manufacture process (instance 4.3)
Except following variation, it is identical that process and top instance 4.1 and 4.2 are mentioned.
Replace pregelatinized Starch with Pulvis Talci in the step 4, and replace polyvidone with hyprolose.
Manufacture process (list of references 1)
Identical with the process of instance 4.1, except the neutral spherolite of use useless (NPS) in step 3; Described quantity is with the microcrystalline Cellulose compensation of proportional amount.
Manufacture process (list of references 2)
Identical with the process of instance 4.1, except in step 4, not using polyvidone.Sheet is reused other composition adjustment.
Manufacture process (list of references 3)
Identical with the process of instance 4.1, except in step 3 and step 4, not using neutral spherolite (NPS) and polyvidone respectively.Final sheet is reused other compositions such as Polyethylene Glycol and microcrystalline Cellulose adjustment.
Instance 5-Lansoprazole intestine orally disintegrating tablet
Instance 6-metroprolol succinate sustained-release sheet
Table 5 has shown the compositions of instance 5 and instance 6
Table 5
There is the problem of mentioning in+expression
There is not the problem of mentioning in-expression
Lansoprazole delays the manufacture process of releasing piece:
1, with mannitol and microcrystalline Cellulose mixing and #36 number sieve of mistake.
2, the enteric piller of step 18 in the instance 2 is crossed the #20 mesh sieve.
3, will be mixed together from the content and the neutral spherolite
of step 1, step 2.
4, Polyethylene Glycol (Macrogol 6000), polyvinylpyrrolidone (Povidone K-90), pregelatinized Starch and silica gel are crossed the #36 mesh sieve.
5, with the raw material of step 3 with from the raw materials mix of step 4 10 minutes.
6, will use suitable mould tabletting at tablet machine from the lubriation material that step 5 obtains.
The manufacture process of metoprolol sustained-release sheet:
1, with polyvinylpolypyrrolidone and microcrystalline Cellulose mixing and mistake #36 mesh sieve.
2, the metoprolol sustained-release piller of step 14 in the instance 3 is crossed suitable # mesh sieve.
3, will be mixed together from the content and the neutral spherolite
of step 1, step 2.
4, Polyethylene Glycol (Macrogol 6000), polyvinylpyrrolidone (Povidone K-90), pregelatinized Starch and silica gel are crossed the #36 mesh sieve.
5, with the raw material of step 3 and raw materials mix time enough from step 4.
6, will use suitable mould tabletting at tablet machine from the lubriation material that step 5 obtains.
Claims (14)
1. a Tableted compositions comprises that (a) comprises the coating multiple-unit of at least a active constituents of medicine and at least a function coating; (b) at least a compressibility reinforcing agent that comprises neutral spherolite; (c) at least a viscosity imparting agent that comprises adhesive; And (d) alternatively, other tabletting adjuvants.
2. Tableted compositions according to claim 1, wherein said active constituents of medicine is selected from esomeprazole, omeprazole, lansoprazole, olanzapine and metoprolol.
3. Tableted compositions according to claim 1 and 2, wherein said function coating is selected from following group, and said group comprises enteric coating, sustained release coating, taste masking coating, stable delivery coating and sealing coating, or their combination.
4. according to any one described Tableted compositions of claim 1 to 3, wherein said neutral spherolite is selected from following group, and said group comprises cane sugar type, microcrystalline Cellulose type, silica-type, glass mould, polypropylene type and corn starch type, or their combination.
5. Tableted compositions according to claim 4, wherein said neutral spherolite is a cane sugar type.
6. according to any one described Tableted compositions of claim 1 to 5; Wherein said adhesive is selected from following group; Said group comprises polyvinylpyrrolidone, vinyl arsenic pyrrolidone vinyl acetate copolymer, hydroxypropyl emthylcellulose and hyprolose, or their combination.
7. Tableted compositions according to claim 6, wherein said adhesive are polyvinylpyrrolidone.
8. according to any one described Tableted compositions of claim 1 to 7, it heavily is 20% to 60% that the weight that wherein said coating multiple-unit constitutes accounts for total sheet.
9. according to any one described Tableted compositions in the claim 1 to 8, it heavily is 2% to 40% that the weight that wherein said neutral spherolite constitutes accounts for total sheet.
10. according to any one described Tableted compositions in the claim 1 to 9, it heavily is 0.5% to 15% that the weight that wherein said adhesive constitutes accounts for total sheet.
11. according to any one described Tableted compositions in the claim 1 to 10, wherein said other tabletting adjuvants are selected from filler, disintegrating agent, buffer agent, fluidizer, antitack agent and lubricant.
12. according to any one described Tableted compositions in the claim 1 to 11, wherein the ratio of compressibility reinforcing agent and viscosity imparting agent is 2:1 to 8:1.
13. the manufacturing approach of the described Tableted compositions of above-mentioned any one claim comprises step:
(a) with active component coating inertia ball core; (b) the ball core of active component coating is used one or more stratum disjunctum coatings, (c) with the function coating ball core coating of coating stratum disjunctum, and said ball core is dry; (d) with the ball core of function coating and neutral spherolite, adhesive and alternatively filler mix; (e) alternatively, buffer agent is mixed with disintegrating agent, lubricant and antitack agent respectively, (f) alternatively the product of step (d) and step (e) is mixed; (g) last, will be from step (d) or the mixture that (f) obtains tabletting on tablet machine.
14. aforesaid right requires the manufacturing approach of any one described Tableted compositions in 3 to 12 to comprise step:
(a) on inertia ball core, carry out sealed packet clothing layer coating, and then the ball core that seals coating is carried out coating, (b) use one or more stratum disjunctums being carried out coating by the ball core of active component coating with active component; (c) with the function coating ball core coating of coating stratum disjunctum; And said ball core is dry, (d) with the ball core of function coating and neutral spherolite, adhesive and alternatively filler mix, (e) alternatively; Buffer agent is mixed with disintegrating agent and antitack agent respectively; (f) product of step (d) and step (e) is mixed, (g) last, mixture tabletting on tablet machine that will obtain from step (f).
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN1136DE2010 | 2010-05-15 | ||
| IN1136/DEL/2010 | 2010-05-15 | ||
| PCT/IB2011/000806 WO2011144975A1 (en) | 2010-05-15 | 2011-04-12 | Multi-unit compositions |
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| Publication Number | Publication Date |
|---|---|
| CN102762198A true CN102762198A (en) | 2012-10-31 |
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| CN2011800100428A Pending CN102762198A (en) | 2010-05-15 | 2011-04-12 | Multi-unit compositions |
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| WO (1) | WO2011144975A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103720671A (en) * | 2014-01-03 | 2014-04-16 | 中国药科大学 | Enteric preparation for proton pump inhibitor and preparation method thereof |
| CN107666913A (en) * | 2015-03-03 | 2018-02-06 | 萨尼奥纳有限责任公司 | Te Suofenxin, beta-blocker combination preparation |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016174664A1 (en) | 2015-04-29 | 2016-11-03 | Dexcel Pharma Technologies Ltd. | Orally disintegrating compositions |
| US10076494B2 (en) | 2016-06-16 | 2018-09-18 | Dexcel Pharma Technologies Ltd. | Stable orally disintegrating pharmaceutical compositions |
| WO2018098434A1 (en) * | 2016-11-28 | 2018-05-31 | Johnson & Johnson Consumer Inc. | Process for making a coated dosage form |
| EP4070789A4 (en) * | 2020-01-23 | 2024-01-24 | Hanmi Pharm Ind Co Ltd | Pharmaceutical composite formulation comprising proton pump inhibitor and antacid |
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| EP0418596A2 (en) * | 1989-09-21 | 1991-03-27 | American Cyanamid Company | Controlled release pharmaceutical compositions from spherical granules in tabletted oral dosage unit form. |
| CN1134666A (en) * | 1994-07-08 | 1996-10-30 | 阿斯特拉公司 | Multiple unit tableted dosage form I |
| US5780055A (en) * | 1996-09-06 | 1998-07-14 | University Of Maryland, Baltimore | Cushioning beads and tablet comprising the same capable of forming a suspension |
| WO2001034684A1 (en) * | 1999-11-12 | 2001-05-17 | R.P. Scherer Technologies, Inc. | Microcrystalline cellulose cushioning granules |
| WO2008006534A2 (en) * | 2006-07-11 | 2008-01-17 | Lek Pharmaceuticals D.D. | Multiple unit tablets |
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2011
- 2011-04-12 CN CN2011800100428A patent/CN102762198A/en active Pending
- 2011-04-12 WO PCT/IB2011/000806 patent/WO2011144975A1/en active Application Filing
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0418596A2 (en) * | 1989-09-21 | 1991-03-27 | American Cyanamid Company | Controlled release pharmaceutical compositions from spherical granules in tabletted oral dosage unit form. |
| CN1134666A (en) * | 1994-07-08 | 1996-10-30 | 阿斯特拉公司 | Multiple unit tableted dosage form I |
| US5780055A (en) * | 1996-09-06 | 1998-07-14 | University Of Maryland, Baltimore | Cushioning beads and tablet comprising the same capable of forming a suspension |
| WO2001034684A1 (en) * | 1999-11-12 | 2001-05-17 | R.P. Scherer Technologies, Inc. | Microcrystalline cellulose cushioning granules |
| WO2008006534A2 (en) * | 2006-07-11 | 2008-01-17 | Lek Pharmaceuticals D.D. | Multiple unit tablets |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103720671A (en) * | 2014-01-03 | 2014-04-16 | 中国药科大学 | Enteric preparation for proton pump inhibitor and preparation method thereof |
| CN107666913A (en) * | 2015-03-03 | 2018-02-06 | 萨尼奥纳有限责任公司 | Te Suofenxin, beta-blocker combination preparation |
| CN107666913B (en) * | 2015-03-03 | 2021-11-26 | 萨尼奥纳有限责任公司 | Tesofensine, beta-receptor blocker combination formulations |
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| WO2011144975A1 (en) | 2011-11-24 |
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