CN101057837B - Dextro-ketoprofen enteric coated preparation and its preparation method - Google Patents
Dextro-ketoprofen enteric coated preparation and its preparation method Download PDFInfo
- Publication number
- CN101057837B CN101057837B CN2006100315223A CN200610031522A CN101057837B CN 101057837 B CN101057837 B CN 101057837B CN 2006100315223 A CN2006100315223 A CN 2006100315223A CN 200610031522 A CN200610031522 A CN 200610031522A CN 101057837 B CN101057837 B CN 101057837B
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- China
- Prior art keywords
- micropill
- dexketoprofen
- sodium lauryl
- enteric
- lauryl sulphate
- Prior art date
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Links
- 229960000991 ketoprofen Drugs 0.000 title abstract description 15
- 238000002360 preparation method Methods 0.000 title description 26
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims abstract description 32
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims abstract description 32
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims abstract description 32
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims abstract description 23
- 229960002783 dexketoprofen Drugs 0.000 claims description 43
- DKYWVDODHFEZIM-NSHDSACASA-N dexketoprofen Chemical compound OC(=O)[C@@H](C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-NSHDSACASA-N 0.000 claims description 43
- 235000010603 pastilles Nutrition 0.000 claims description 41
- 238000007789 sealing Methods 0.000 claims description 33
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 31
- 239000004141 Sodium laurylsulphate Substances 0.000 claims description 31
- 235000019333 sodium laurylsulphate Nutrition 0.000 claims description 31
- 229920002472 Starch Polymers 0.000 claims description 15
- 239000008107 starch Substances 0.000 claims description 15
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 14
- 229930006000 Sucrose Natural products 0.000 claims description 14
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 14
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 14
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 14
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 14
- 239000000203 mixture Substances 0.000 claims description 14
- 235000019698 starch Nutrition 0.000 claims description 14
- 239000005720 sucrose Substances 0.000 claims description 14
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 claims description 10
- 239000002775 capsule Substances 0.000 claims description 9
- 239000006185 dispersion Substances 0.000 claims description 9
- 229960003943 hypromellose Drugs 0.000 claims description 9
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 claims description 8
- 229920003145 methacrylic acid copolymer Polymers 0.000 claims description 8
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- 235000013769 triethyl citrate Nutrition 0.000 claims description 8
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 claims description 8
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 claims description 4
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 claims 3
- 229960001680 ibuprofen Drugs 0.000 claims 3
- 150000002576 ketones Chemical class 0.000 claims 3
- 239000001828 Gelatine Substances 0.000 claims 1
- 229920000159 gelatin Polymers 0.000 claims 1
- 235000019322 gelatine Nutrition 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 21
- 238000000034 method Methods 0.000 abstract description 9
- 239000003795 chemical substances by application Substances 0.000 abstract description 5
- DKYWVDODHFEZIM-UHFFFAOYSA-N ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 abstract description 5
- 210000001035 gastrointestinal tract Anatomy 0.000 abstract description 4
- 238000007493 shaping process Methods 0.000 abstract 3
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- 230000000638 stimulation Effects 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- 238000012216 screening Methods 0.000 description 17
- 239000012055 enteric layer Substances 0.000 description 15
- 239000000546 pharmaceutical excipient Substances 0.000 description 15
- 238000003756 stirring Methods 0.000 description 12
- 239000000463 material Substances 0.000 description 11
- 238000000576 coating method Methods 0.000 description 9
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 230000000694 effects Effects 0.000 description 8
- 238000002474 experimental method Methods 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- 239000011230 binding agent Substances 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- 239000002702 enteric coating Substances 0.000 description 7
- 238000009505 enteric coating Methods 0.000 description 7
- 239000008187 granular material Substances 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 238000001035 drying Methods 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 239000008188 pellet Substances 0.000 description 6
- 210000002784 stomach Anatomy 0.000 description 6
- 239000011248 coating agent Substances 0.000 description 5
- 235000019441 ethanol Nutrition 0.000 description 5
- -1 pla-pcl Substances 0.000 description 5
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 5
- 229920000053 polysorbate 80 Polymers 0.000 description 5
- 239000002002 slurry Substances 0.000 description 5
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 4
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 4
- 229960000935 dehydrated alcohol Drugs 0.000 description 4
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- 230000000968 intestinal effect Effects 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 206010070840 Gastrointestinal tract irritation Diseases 0.000 description 3
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- 229920005989 resin Polymers 0.000 description 3
- 238000005507 spraying Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 2
- 208000032843 Hemorrhage Diseases 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 238000009825 accumulation Methods 0.000 description 2
- 230000000202 analgesic effect Effects 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
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- 210000001198 duodenum Anatomy 0.000 description 2
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- 230000002496 gastric effect Effects 0.000 description 2
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 2
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- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
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- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 206010059024 Gastrointestinal toxicity Diseases 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 description 1
- 229930064664 L-arginine Natural products 0.000 description 1
- 235000014852 L-arginine Nutrition 0.000 description 1
- 206010061297 Mucosal erosion Diseases 0.000 description 1
- 208000004550 Postoperative Pain Diseases 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- 206010053692 Wound complication Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- RZAPELUKMZWLLG-UHFFFAOYSA-N acetic acid;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound CC(O)=O.CC(O)=O.CC(O)=O.OC(=O)CC(O)(C(O)=O)CC(O)=O RZAPELUKMZWLLG-UHFFFAOYSA-N 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000001741 anti-phlogistic effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
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- 201000006549 dyspepsia Diseases 0.000 description 1
- 239000002662 enteric coated tablet Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
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- 239000011229 interlayer Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
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- 238000006386 neutralization reaction Methods 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-N o-dicarboxybenzene Natural products OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 1
- 229960005489 paracetamol Drugs 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229960002895 phenylbutazone Drugs 0.000 description 1
- VYMDGNCVAMGZFE-UHFFFAOYSA-N phenylbutazonum Chemical compound O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=CC=C1 VYMDGNCVAMGZFE-UHFFFAOYSA-N 0.000 description 1
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Landscapes
- Medicinal Preparation (AREA)
Abstract
The invention provides an enteric soluble micro-pill agent of clockwise ketoprofen and the preparing method, comprising medicine-containing micro-pill composed of clockwise ketoprofen and one or more than one kind of medical shaping agent, insulating layer composed of hydroxypropylmethylcellulose and other medical shaping agent, and enteric soluble layer made by one or more than one kind of medical shaping agent. The product is characterized by even medicine release, high biological utilization rate and small stimulation to gastrointestinal tract.
Description
Technical field
The invention belongs to the Western medicine invention field, relate to good enteric coated preparation of a kind of 2-aryl propionic non-steroid antiphlogistic chipal compounds dexketoprofen and preparation method thereof.
Background technology
Dexketoprofen is the active dextroisomer of ketoprofen, by the exploitation of Italian Menarini company, went on the market in Spain first in 1996, has good antiinflammatory, analgesic and analgesic effect, and effect is better than aspirin, Phenylbutazone or acetaminophen etc., be widely used in the treatment of chronic rheumatoid arthritis, osteoarthrisis deformans knee, wound and postoperative pain at present, enjoy various countries clinician and patient's favor because of its good curative effect.
Yet the shortcoming of NSAID (non-steroidal anti-inflammatory drug) maximum is gastrointestinal tract toxic and side effects such as damage stomach and duodenum.Compare with the racemization ketoprofen, though dexketoprofen dosage on identical drug effect level is littler, less adverse effect, clinical practice is wider, but still does not break away from some shortcomings similar to ketoprofen, as is insoluble in water, absorbs relatively poorly, and gastrointestinal toxicity is bigger etc.Especially damage stomach and duodenum, high 5 times (its reason mainly is suppressed the gastrointestinal wall prostaglandin synthetic to the hemorrhage rate of user's upper gastro-intestinal tract than user not, the physicochemical characteristics of medicine can cause aggravating toxicity etc. in the drug accumulation of coat of the stomach), so influence its potential applicability in clinical practice.The preparation of using clinically mostly is common enteric coated tablet or capsule at present, has limited dexketoprofen and has brought into play quick refrigeration function, also can not fundamentally address the above problem.The dextro-ketoprofen enteric coated above-mentioned deficiency that overcome involved in the present invention both can reduce GI irritation, had controlled release and targeted therapy effect again, was a kind of novel good enteric coated preparation of dexketoprofen.
Summary of the invention
It is even that purpose of the present invention aims to provide a kind of release, and the bioavailability height is to little dextro-ketoprofen enteric coated of GI irritation, to solve the problems such as gastrointestinal tract toxic and side effects of dexketoprofen.
Another object of the present invention aims to provide a kind of preparation method of good enteric coated preparation of dexketoprofen.
The objective of the invention is to realize by following manner:
Enteric coated micropill of the present invention comprises the pastille micropill be made up of dexketoprofen and one or more pharmaceutically useful excipient, the sealing coat of being made up of hydroxypropyl methylcellulose and other pharmaceutically useful excipient and the enteric layer of being made up of one or more pharmaceutically useful excipient.
Described pastille micropill also can be made by celphere and dexketoprofen and one or more pharmaceutically acceptable excipient of being deposited on this celphere.
The excipient that the pastille micropill is adopted is one or more in hydroxypropyl methylcellulose, sodium lauryl sulphate, carboxymethyl starch sodium, polyvidone, microcrystalline Cellulose, starch, L-arginine, pla-pcl, carboxymethyl cellulose phthalic acid ester, plant gum, wax, nonreducing sugar such as the sucrose; Described sealing coat contains one or more in Pulvis Talci, magnesium stearate, crosslinked ketopyrrolidine, hydroxypropyl methylcellulose, sodium lauryl sulphate, non-reducing sugar such as the sucrose; Enteric layer contain in the pharmaceutically acceptable excipient of promising crylic acid resin such as methacrylic acid copolymer aqueous dispersion, Pulvis Talci, citric acid triacetic acid, tween 80, the sodium lauryl sulphate one or more.
Contain the 2.5-30mg dexketoprofen in the enteric coated pellets formulation of the present invention.
It is preferable to contain the 5-20mg dexketoprofen in the enteric coated pellets formulation of the present invention.
The present invention is dextro-ketoprofen enteric coated, and it is good containing following composition:
The pastille micropill
Celphere 70-90mg
Dexketoprofen 12.5mg
Microcrystalline Cellulose 15-30mg
Hydroxypropyl methylcellulose 5-12mg
The sodium lauryl sulphate trace
Sealing coat
Pastille micropill 102.5-152.5mg
The sodium lauryl sulphate trace
Hypromellose 8-20mg
Sucrose 5-15mg
Enteric layer
Sealing coat micropill 115.5-187.5mg
Methacrylic acid copolymer aqueous dispersion 180-250mg
Pulvis Talci 8-18mg
Triethyl citrate 4-9mg
Crosslinked ketopyrrolidine 15-30mg
Sodium lauryl sulphate 4-10mg.
Described celphere contains following composition:
Starch 30-45mg
Microcrystalline Cellulose 30-45mg
Sucrose 10-25mg
Micropill of the present invention contains following composition for best:
The pastille micropill
Celphere 75-80mg
Dexketoprofen 12.5mg
Microcrystalline Cellulose 15-25mg
Hydroxypropyl methylcellulose 5-10mg
The sodium lauryl sulphate trace
Sealing coat
Pastille micropill 112-134mg
The sodium lauryl sulphate trace
Hypromellose 10-15mg
Sucrose 8-12mg
Enteric layer
Sealing coat micropill 130-160mg
Methacrylic acid copolymer aqueous dispersion 2 00-225mg
Pulvis Talci 10-15mg
Triethyl citrate 5-8mg
Crosslinked ketopyrrolidine 20-25mg
Sodium lauryl sulphate 4-8mg.
The preparation method of micropill of the present invention is: A, provide the pastille micropill of being made up of dexketoprofen and one or more pharmaceutically useful excipient; B, on the pastille micropill, apply the sealing coat that one deck contains one or more pharmaceutically acceptable excipient; D, on sealing coat, apply the enteric layer that one deck contains hydroxypropyl methylcellulose and one or more pharmaceutically acceptable excipient.
The untoward reaction of dexketoprofen is an injury of gastrointestinal tract, and hemorrhage as dyspepsia, mucosal erosion, gastric and duodenal ulcers, severe patient can cause perforation etc.This is the modal untoward reaction of non-steroidal antibiotic.The present invention is after carrying out scrutiny by the preparation process to dexketoprofen, adopt advanced preparation process that dexketoprofen is prepared into enteric coated micropill, then above-mentioned enteric coated micropill is filled in the common enteric coated capsule and is prepared from, can avoid like this occurring causing the phenomenon that local drug concentration is too high when common enteric dosage form discharges in intestinal, will have significant clinical superiority.But said preparation is to the manufacturing technique requirent height, and this medicine is not changed when the stomach by the patient, and can dissolve rapidly and release of active ingredients when it leaves stomach and enters small intestinal.Active component wherein is in the inside of micropill and wraps in thin film or tunicle promptly in " enteric coating ".Described enteric coating is insoluble in sour environment such as stomach, and is soluble in nearly neutral environment such as small intestinal.
Enteric coated pellets formulation involved in the present invention has been concentrated the advantage of pellet preparations, two kinds of dosage forms of enteric coated preparation, thereby makes the medicine release even, and the bioavailability height is little to GI irritation.
The specific embodiment
The various compositions and the layer of micropill below will be discussed respectively, and the concrete simultaneously various compositions of interpolation of introducing progressively make up dextro-ketoprofen enteric coated method.
Pastille micropill among the present invention can directly be prepared from by dexketoprofen and one or more pharmaceutically useful excipient.Also another kind of mode be can adopt, dexketoprofen and excipient on celphere, applied.
Preferred pastille micropill is coated on the celphere by the interlayer that will contain dexketoprofen and is prepared.Described celphere is that pharmaceutical field can be bought or make by oneself.The most preferred celphere of the present invention be the starch that is used for drug manufacture, microcrystalline Cellulose and hydroxypropyl methylcellulose preparation and the ball core.Yet, the hollow ball core that also can use any pharmaceutically acceptable excipient to make, described excipient comprises for example sucrose, wax, plant gum etc.Be primarily characterized in that be inert for the patient of other excipient in dexketoprofen and the micropill and this micropill that will take.
The size of pastille micropill depends on the required size of micropill to be produced.Usually, micropill can be as small as 0.1mm or greatly to 2mm.Preferred nuclear core is 0.2mm to 1.0mm, so as finally to obtain required preferred size, diameter is the micropill of about 0.5-1.5mm.
The amount of used pastille micropill depends on the weight and the thickness of the interpolation layer beyond the pastille micropill, and usually, the pastille micropill accounts for the 10-70% of product.More preferably the pastille micropill accounts for about 15-45% of product.
The preparation process of enteric coated micropill involved in the present invention comprises the preparation of dexketoprofen pastille micropill, sealing coat coated micropill and enteric coated micropill.Step is as follows: the preparation of A, dexketoprofen pastille micropill: with the celphere is carrier, and proper auxiliary materials such as sodium lauryl sulphate are dissolved in the suitable quantity of water, and the adding dexketoprofen stirs to make and is uniformly dispersed, and adds an amount of dehydrated alcohol, stirs; Hydroxypropyl methylcellulose is disperseed with an amount of ethanol, be prepared into solution or suspension with certain bonding force, even spraying is coated in hollow ball core outside, makes that micropill increases under the state of rotation that rolls, drying, forms the pastille micropill.B, the preparation of dexketoprofen sealing coat micropill: hydroxypropyl methylcellulose, sodium lauryl sulphate etc. is mixed with coating solution, pastille nuclear core is carried out isolation coat.C, dextro-ketoprofen enteric coated preparation: Pulvis Talci, triethyl citrate, tween 80 etc. are mixed with enteric coating liquid, will wrap the sealing coat micropill and carry out enteric coating.
Is " powder coating method " with dexketoprofen to the method that makes things convenient for that celphere carries out coating, in the method, celphere with thick liquid or binding agent moistening, is made the medicine slurry with the dexketoprofen powder of crushing screening and sparged on the celphere, then with the mixture drying.This method is used in the industrialization drug manufacture usually, and suitable device is a usual means.All used this device in many steps of the inventive method, also available fluidized bed plant or rotating plate device prepare product of the present invention.
The preparation of dexketoprofen pastille micropill also can be as follows: proper auxiliary materials such as sodium lauryl sulphate, microcrystalline Cellulose, starch etc. are dissolved in the suitable quantity of water, add dexketoprofen and stir to make and be uniformly dispersed, add an amount of dehydrated alcohol, stir; Hydroxypropyl methylcellulose is disperseed with an amount of ethanol, be prepared into solution or suspension with certain bonding force, granulate, sieve, the granule of getting between the 50-60 order is a parent nucleus, rest materials is suspended in the binding agent, even spraying is coated in parent nucleus outside, makes that micropill increases under the state of rotation that rolls, drying, forms the pastille micropill.
Among the present invention various excipient determine it all is that the inventor passes through repeatedly to test, update and the principal agent dexketoprofen suitable of the present invention that obtains, can better prepare the proper auxiliary materials of micropill of the present invention.The inventor also further obtains being fit to best proportioning of the present invention by following experiment.Below done experiment, so that determine corresponding auxiliary material of the present invention better by the inventor.
Because roundness, the friability of celphere directly influence drug of topical application effect, thereby influence the content and the quality of pastille micropill, so select suitable blank core ball material extremely important.The inventor considers the microcrystalline Cellulose stable in properties, and good moldability and chance water have expansion, do not influence the release of medicine; Starch has certain mouldability, has certain disintegrate effect concurrently; Sucrose has hygroscopicity to be easy to into granule.Therefore, the inventor drafts from these three kinds of adjuvants the material of screening preparation celphere by experiment, as binding agent, and screens preferable solvent and concentration thereof simultaneously with the fine little element of hydroxypropyl methyl.
The celphere prescription screening
Draft the screening prescription, see Table 1.
The screening prescription of table 1 celphere
Through the above result of analysis-by-synthesis, prescription three is more excellent.
After making the celphere preparation, be that other composition of pastille micropill is determined with that.The inventor considers that with the fine little element of hydroxypropyl methyl be binding agent, and screens its concentration by experiment; The disintegrate of medicine and release for the benefit of, we add the microcrystalline Cellulose with disintegration in medicated layer, add an amount of sodium lauryl sulphate to increase the lubricity of medicine slurry, produce static when preventing to produce, and help the release of medicine.Screen medicine by experiment and starch the consumption of each component,, purpose ball yield whether bright and clean with balling-up, hardness, the surface of pastille micropill, result of extraction are index, determine the best composition and the ratio of medicine slurry.
The prescription screening of pastille micropill medicinal liquid
Draft the screening prescription, see Table 2:
The screening prescription of table 2 pastille micropill medicinal liquid
Behind the analysis-by-synthesis, found that prescription four is more excellent, and by experiment it is verified.
The inventor determines to have carried out further exploratory development to the prescription of sealing coat.
Because the dexketoprofen raw material is stable under alkali condition among the present invention, extremely unstable under acid condition, so consider bag sealing coat earlier, wrap enteric layer again.The sealing coat of this product adopts film property hydroxypropyl emthylcellulose preferably, sealing coat weightening finish 5%, and the inventor also further screens its suitable concentration by experiment.Phenomenon, film property, yield, dissolution with the coating process of micropill are index, determine the preferred plan of sealing coat.
The screening of sealing coat coating fluid prescription
Draft the screening prescription and see Table 3:
Table 3 sealing coat coating fluid prescription screening table
Comprehensive analysis results is found the prescription three micropill sealing coat best results of wrapping, and yield reaches 98%.
Be that the inventor explores enteric layer prescription screening and research at last.
Concrete condition according to the coating process is improved, with the material state of micropill coating process, film property, 2 hours releases, yields are that index is screened in the phosphate buffer of 1 hour and pH value 6.8 in hydrochloric acid solution (9 → 1000) 900ml, to determine best prescription and technology.
The prescription screening of enteric coating liquid sees Table 4.
The prescription screening table of table 4 enteric coating liquid
5.4 enteric liquid prescription screening the results are shown in Table 5:
Table 5 enteric liquid prescription screening result
The above result of analysis-by-synthesis, gained enteric coated-pellet film property, material whitewashing state is all fine.Take the release of three prescription gained micropills in sour neutralization buffer into consideration, for guaranteeing the quality of the pharmaceutical preparations, the inventor selects to adopt prescription two to be the prescription of this preparation enteric coating coating solution, enteric layer weightening finish 35%.And by experiment it is verified that yield reaches 95.1%, and gained micropill release in acid is 0.73%, and release is 97.4% in buffer, and the accumulation dissolution is 98.7%, and is effective, reached Expected Results.
Embodiment 1:
12.5mg dextro-ketoprofen enteric coated capsule
Stock chart
The pastille micropill
Celphere 90mg (30-40 order)
Dexketoprofen 12.5mg
The sodium lauryl sulphate trace
Hydroxypropyl methylcellulose 7.5mg
Microcrystalline Cellulose 20mg
Sealing coat
Pastille micropill 130mg
The sodium lauryl sulphate trace
Hypromellose 12mg
Sucrose 10mg
Enteric layer
Sealing coat micropill 152mg
Methacrylic acid copolymer aqueous dispersion 245mg
Pulvis Talci 12mg
Triethyl citrate 6mg
Sodium lauryl sulphate 6mg
Take by weighing hydroxypropyl methylcellulose and add absolute ethyl alcohol and stirring and make and be uniformly dispersed, add purified water and make it abundant swelling, sieve, as binding agent.The microcrystalline Cellulose pulverizing is sieved, take by weighing starch and its mix homogeneously, granulate, sieve, the granule of getting between the 50-60 order is a parent nucleus, and rest materials is suspended in the binding agent, crosses 80 mesh sieves, is sprayed on the parent nucleus, and oven dry is sieved, and is the purpose ball with 30-40 order ball core.
Sodium lauryl sulphate is dissolved in the suitable quantity of water, and the dexketoprofen that adds crushing screening stirs to make and is uniformly dispersed, and adds an amount of dehydrated alcohol, stirs; In addition hypromellose is disperseed with an amount of ethanol, add microcrystalline Cellulose and be uniformly dispersed; Above-mentioned two solution stirring are made into the homogeneous system, sieve and make the medicine slurry.Medicine slurry with the suspension sample that obtains is coated on the hollow micropill of microcrystalline Cellulose-starch then.After having applied the dexketoprofen suspension of aequum, with pastille micropill drying.
Sodium lauryl sulphate is dissolved in the suitable quantity of water, its aqueous solution is joined in the alcohol dispersion liquid of hydroxypropyl methylcellulose, stirring makes the hydroxypropyl methylcellulose complete swelling to even,
Pulvis Talci, triethyl citrate, sodium lauryl sulphate are added homogenate in the pure water successively, suspension after the homogenate is added in the methacrylic acid copolymer aqueous dispersion, stirring makes into uniform suspension, sieve, form with aqueous suspension is coated to enteric layer on the micropill of sealing coat then, behind the suspension that has applied aequum, with the micropill finish-drying.Promptly get enteric coated micropill.
Analyze the content of dexketoprofen in the gained micropill, and fill it in the capsulae vacuus to obtain containing the enteric-coated pellet capsule of 12.5mg dexketoprofen.
Embodiment 2:
12.5mg dextro-ketoprofen enteric coated capsule
Stock chart
The pastille micropill
Sucrose 90mg
Hydroxypropyl methylcellulose 25mg
Dexketoprofen 12.5mg
The sodium lauryl sulphate trace
Carboxymethyl starch sodium 25mg
Sealing coat
Pastille micropill 152.5mg
Hypromellose 20mg
Magnesium stearate 24mg
The sodium lauryl sulphate trace
Enteric layer
Sealing coat micropill 196.5mg
No. 2 resin 30mg
Pulvis Talci 20mg
Tween 80 0.08ml
Sucrose, carboxymethyl starch sodium etc. is dissolved in the suitable quantity of water, and the adding dexketoprofen stirs to make and is uniformly dispersed, and adds an amount of dehydrated alcohol, stirs; Hydroxypropyl methylcellulose is disperseed with an amount of ethanol, be prepared into solution or suspension with certain bonding force, granulate, sieve, the granule of getting between the 50-60 order is a parent nucleus, rest materials is suspended in the binding agent, even spraying is coated in parent nucleus outside, makes that micropill increases under the state of rotation that rolls, drying, forms the pastille micropill.
It is described then to press the foregoing description 1, respectively sealing coat and enteric layer is applied up, is prepared into micropill.
Embodiment 3:
12.5mg dextro-ketoprofen enteric coated capsule
Stock chart
The pastille micropill
Celphere (sucrose 75mg, hydroxypropyl methylcellulose 10mg) 30-40 orders
Dexketoprofen 12.5mg
The sodium lauryl sulphate trace
Hydroxypropyl methylcellulose 25mg
Sealing coat
Pastille micropill 122.5mg
Titanium dioxide 12mg
Hypromellose 20mg
Polyvidone 18mg
Enteric layer
Sealing coat micropill 172.5mg
Enteric resin 15mg
Triethyl citrate 6mg
Magnesium stearate 15mg
Embodiment 4
Celphere
Microcrystalline Cellulose 25mg
Starch 60mg
Hydroxypropyl methylcellulose 5mg
The pastille micropill
Celphere 85mg
Dexketoprofen 12.5mg
The sodium lauryl sulphate trace
Hydroxypropyl methylcellulose 10mg
Carboxymethyl starch sodium 30mg
Sealing coat
Pastille micropill 137.5mg
The sodium lauryl sulphate trace
Hypromellose 20mg
Enteric layer
Sealing coat micropill 157.5mg
Methacrylic acid copolymer aqueous dispersion 180mg
Pulvis Talci 15mg
Tween 80 0.05ml
Sodium lauryl sulphate 9g.
Other step is substantially with embodiment 1.
Embodiment 5
The pastille micropill
Sucrose 30mg
Starch 60mg
L-arginase 12 0mg
Dexketoprofen 12.5mg
The sodium lauryl sulphate trace
Hydroxypropyl methylcellulose 10mg
Sealing coat
Pastille micropill 132.5mg
The sodium lauryl sulphate trace
Hypromellose 25mg
Enteric layer
Sealing coat micropill 157.5mg
Methacrylic acid copolymer aqueous dispersion 250mg
Triethyl citrate 9mg
Tween 80 0.05ml
Sodium lauryl sulphate 9g.
Substantially can prepare this product by the foregoing description 1 method therefor.Gained micropill and capsule administration field method commonly used detects, and the equal quality of sample is stable.
Clinical and experimental study shows, micropill of the present invention and capsule not only have the characteristics of conventional enteric coated preparation, when also having the generic condition that micropill touches small intestinal, can discharge contained dexketoprofen rapidly equably, thereby solve the too high problem of local drug concentration that general enteric dosage form is run into.
Claims (3)
1. dextrorotation ketone ibuprofen enteric coated micropill is characterized in that containing following composition:
Sealing coat coated micropill 115.5-187.5mg
Methacrylic acid copolymer aqueous dispersion 180-250mg
Pulvis Talci 8-18mg
Triethyl citrate 4-9mg
Crosslinked ketopyrrolidine 15-30mg
Sodium lauryl sulphate 4-10mg
Wherein said sealing coat coated micropill is:
Pastille micropill 102.5-152.5mg
The sodium lauryl sulphate trace
Hypromellose 8-20mg
Sucrose 5-15mg
Wherein said pastille micropill is:
Celphere, 30-35 order 70-90mg
Dexketoprofen 12.5mg
Microcrystalline Cellulose 12-30mg
Hydroxypropyl methylcellulose 5-12mg
The sodium lauryl sulphate trace.
2. dextrorotation ketone ibuprofen enteric coated micropill according to claim 1, it is characterized in that: described celphere contains following composition:
Starch 30-45mg
Microcrystalline Cellulose 30-45mg
Sucrose 10-25mg.
3. one kind contains the gelatine capsule that right requires 1 or 2 described dextrorotation ketone ibuprofen enteric coated micropills.
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| Application Number | Priority Date | Filing Date | Title |
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| CN2006100315223A CN101057837B (en) | 2006-04-20 | 2006-04-20 | Dextro-ketoprofen enteric coated preparation and its preparation method |
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| Application Number | Priority Date | Filing Date | Title |
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| CN2006100315223A CN101057837B (en) | 2006-04-20 | 2006-04-20 | Dextro-ketoprofen enteric coated preparation and its preparation method |
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| CN101057837B true CN101057837B (en) | 2010-12-22 |
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| CN110917165A (en) * | 2019-12-26 | 2020-03-27 | 北京鑫开元医药科技有限公司海南分公司 | Ibuprofen orally disintegrating tablet and preparation method thereof |
| CN112641756B (en) * | 2020-12-29 | 2022-08-19 | 卓和药业集团股份有限公司 | Posaconazole enteric-coated pellet and preparation method thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1200924A (en) * | 1997-05-29 | 1998-12-09 | 伊莱利利公司 | Fluoxetine enteric micropills |
| CN1260172A (en) * | 1998-12-18 | 2000-07-19 | 国家医药管理局上海医药工业研究院 | Dextro-betoprofen preparation |
| CN1546025A (en) * | 2003-12-12 | 2004-11-17 | 南京长澳医药科技有限公司 | Enteric-coated pantoprazole sodium minipill |
| CN1759829A (en) * | 2004-10-14 | 2006-04-19 | 上海医药工业研究院 | Duloxetine enteric coated tiny pill capsule, and preparation method |
-
2006
- 2006-04-20 CN CN2006100315223A patent/CN101057837B/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1200924A (en) * | 1997-05-29 | 1998-12-09 | 伊莱利利公司 | Fluoxetine enteric micropills |
| CN1260172A (en) * | 1998-12-18 | 2000-07-19 | 国家医药管理局上海医药工业研究院 | Dextro-betoprofen preparation |
| CN1546025A (en) * | 2003-12-12 | 2004-11-17 | 南京长澳医药科技有限公司 | Enteric-coated pantoprazole sodium minipill |
| CN1759829A (en) * | 2004-10-14 | 2006-04-19 | 上海医药工业研究院 | Duloxetine enteric coated tiny pill capsule, and preparation method |
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