CN101073563B - Chiral composition containing dextrothyroxine buprofenli and levomethadyl cysteliqin and its double slow-releasing tablet - Google Patents
Chiral composition containing dextrothyroxine buprofenli and levomethadyl cysteliqin and its double slow-releasing tablet Download PDFInfo
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Abstract
The invention is concerned with a kind of chiral compound and its sustained and controlled release double deck pieces compound with (S)-ibuprofen and levocetirizine. The weight ratio of the both is 50:1 to 500:1, and the said troche has two layers and one layer is the sustained and controlled release part made of (S)-ibuprofen, levocetirizine dihydrochloride and acceptable rapidly release assistant stuff. It can collapse quickly to be absorbed by body to take effect and work with antipyretic and analgesic effects, lighten sneezing, nasal stiffness and rhinocnesmus. The other layer is controlled release layer made on (S)-ibuprofen and acceptable controlled release assistant stuff. It can release with sustained and controlled in body to keep the concentration of blood and medicine in body of (S)-ibuprofen and work with antipyretic and analgesic effects to reduce the symptom of cold.
Description
Technical field
The present invention relates to a kind of pharmaceutical composition for the treatment of flu, particularly a kind of compositions that contains (S)-ibuprofen or its pharmaceutically acceptable salt and levocetirizine dihydrochloride, both weight ratio scopes are 50: 1～500: 1, make the oral double-layer tablet dosage form of releasing slowly that is fit to take.
Background technology
Ibuprofen is a phenylpropionic acid nonsteroidal antipyretic-antalgic anti-inflammatory agent, and its antipyretic-antalgic effect and aspirin, Phenylbutazone are similar, be better than acetaminophen, and gastrointestinal side effect are lighter, better tolerance.Pseudoephedrine has the pressor effect of selectivity, can eliminate the swelling of nasopharynx part mucous hyperemia, alleviates the nasal obstruction symptom.Therefore, ibuprofen and pseudoephedrine are often formed compound oral administration preparation and are widely used in symptoms such as heating that treatment flu causes, headache, extremities aching pain, nasal obstruction.
Yet the safety of Buluoweima oral formulations remains in some unsatisfactory parts, and still there are multiple side effect such as certain GI irritation, platelet/leukopenia, anaphylaxis nephritis, cystitis and bronchospasm in ibuprofen on the one hand; Adrenomimetic drug class nasal congestion abirritant such as pseudoephedrine is forbidden in serious hyperpietic on the other hand, carefully be used for patients such as hypertension, diabetes, glaucoma, thyroid disease and prostate hyperplasia, obviously can not satisfy the medication needs of increasing at present hypertension, diabetics flu both at home and abroad.In addition, pseudoephedrine can be used as the raw material of producing drugs amfebutamone (methamphetamine hydrochloride).It is reported that the U.S. is under the pressure of law enforcement agency and each state government, freely the buying of restriction pseudoephedrine begun to make laws, and since JIUYUE in 2006 30 days, the U.S. has 37 states that patient is bought the OTC flu medicine contain pseudoephedrine, and to make the law of strict restriction formally effective, be that the amount that each consumer buys pseudoephedrine every day must not surpass 3.6g, and must show the certificate that contains photo and carry out registration work, some state also will require to buy with prescription.Be necessary in view of this prescription of existing Buluoweima oral formulations is adjusted.
Similar to pseudoephedrine, U.S. FDA approval in 1976 phenylephrine (10mg/ time) can be used as and alleviates nasal mucosa congestion and edema nonprescription drugs and antipyretic analgesic, the different compound recipe of compositions such as antihistaminic is used for the oral medication flu, as Kodak beautiful jade (sheet), quick of willow phenol coffee (you can fit), phenylephrine brompheniramine capsule (Er Kean), Fluzep Tablet, peaceful (pendant madam) regular convention formula of Common Cold and do not have the sleepiness prescription, plain sheet is coughed in the happiness cold, really agent syrup, cough in the sense formula for a product such as peaceful and all contain phenylephrine hydrochloride, this composition has the upper respiratory tract of contraction blood capillary, eliminate the hyperemia of nasopharynx part mucosa, alleviate effects such as nasal obstruction symptom.Compare with pseudoephedrine, there is phenolic hydroxyl group on the phenylephrine phenyl ring, can improve the affinity of medicine and receptor on the one hand, macromolecule water-solubility increases on the other hand, central nervous system's side effect is less relatively, and phenylephrine is one of to select preferably in the similar nasal mucosa congestion and edema depressant in theory.In order to tackle the law of " purchasing the OTC flu medicine that contains pseudoephedrine " that U.S.'s JIUYUE in 2006 entered into force on the 30th with prescription and certificate registration limit, external each big drugmaker (as U.S. Pfizer company, Johnson-Johnson company etc.) begins to adjust OTC (over-the-counter) coldrex formula for a product, and replace pseudoephedrine with the phenylephrine of identical pharmacological action, as Sudafed PE.Yet phenylephrine is owing to the first pass effect of monoamine oxidase, MAO in the intestinal regulating liver-QI, and oral absorption is less, and it only is 38% that report is arranged, and bioavailability is not high.U.S. Florida university in view of this
Leslie HendelesProfessor and Randy Hatton professor exist
Journal of Allergy and Clinical Immunology(2006; 7) in the letter of delivering that causes editor the effectiveness of traditional 10mg/ dosage is queried.The clinical trial (NCT00276016) of U.S. Schering-Plough company confirms that also 12mg/ phenylephrine is invalid to nasal obstruction due to the pollen hypersensitivity rhinitis, so the said firm's decision substitutes pseudoephedrine composition among its coldrex Claritin-D without phenylephrine.Research worker represents that the oral dose that increases phenylephrine perhaps can reach Expected Results, but drugmaker is necessary to carry out clinical trial at this point, the safety of clear and definite heavy dose of oral phenylephrine and effectiveness.U.S. Senior Expert HenryA.Waxman writes the newly appointed chief Dr.Von of U.S. FDA Eschenbach for 3 times, proposes that FDA revalues the safe and effective dosage of clinical oral administration of phenylephrine.
Although FDA does not make the decision of reappraising phenylephrine as yet at present, but self-examination FDA from the phenylpropanolamine (PPA) of removing the city because of serious adverse reactions such as cardiac toxicity replace with pseudoephedrine, from the pseudoephedrine that can produce the methamphetamine hydrochloride raw material replace with phenylephrine and phenylephrine at present institute face invalid dispute, be enough to allow catch a cold the patient to select which kind of safely and effectively the nasal congestion abirritant feel at a loss as to what to do.
In fact, more existing coldrexs have been avoided using and have been contained adrenomimetic drug class nasal congestion abirritants such as pseudoephedrine or phenylephrine, only keep antihistaminic in the hope of alleviating symptoms such as the caused watery nasal discharge of flu, nose are overworked, sneeze, antihistaminic commonly used has chlorphenamine maleate (chlorphenamine).Similarly coldrex has child bring down a fever sheet (containing acetaminophen, chlorphenamine), pediatric paracetamol,atificial cowbezoar and chlorphenamine maleate granule (acetaminophen, chlorphenamine maleate, artificial Calculus Bovis), Paracetamol and Amantadine Compound (containing acetaminophen, chlorphenamine, amantadine, artificial Calculus Bovis, caffeine), compound recipe zinc cloth granule (containing ibuprofen, chlorphenamine, zinc gluconate) etc.In view of chlorphenamine has drowsiness side effect, so majority replaces with the loratadine of no sedation with it.Though chlorphenamine and loratadine all can effectively be alleviated watery nasal discharge, sneeze that flu causes, but these two kinds of antihistaminics are invalid to having a stuffy nose, have no alternative but or need coupling adrenomimetic drug class nasal congestion abirritant, as Clariflu (containing acetaminophen, loratadine, pseudoephedrine).Therefore, searching can be alleviated nasal obstruction and without the efficient non-sedative antihistamine agent of a new generation of liver drug enzyme influence, is the unique channel of fundamentally evading cardiovascular system side effect risk due to the adrenomimetic drug class nasal congestion abirritant.
The present invention is through research, use (S)-ibuprofen (perhaps pharmaceutically acceptable salt) and can effectively alleviate the novel antihistaminic levorotatory citirizine dihydrochloride compatibility composition new compound of nasal obstruction, more traditional compound recipe Buluoweima treatment flu is more effective, safer, patient crowd is wider, better than both independent results of use simultaneously, have good synergism.
Summary of the invention
The invention provides a kind of new compound flu chiral drug compositions that (S)-ibuprofen or its pharmaceutically acceptable salt and levorotatory citirizine dihydrochloride are formed as active constituents of medicine that contains.
Studies show that recently, (S)-ibuprofen enantiomer are the active component in the raceme ibuprofen, and its pharmacologically active is 160 times of its levo form, are 1.6 times of racemic ibuprofen; And left-handed ibuprofen enantiomer is a non-active ingredient, and relates to potential toxic and side effects.Studies show that the 300mg (S)-ibuprofen is equal to the clinical efficacy of 400mg raceme ibuprofen, and safety, effectiveness and toleration obviously are better than raceme ibuprofen and other NSAID (non-steroidal anti-inflammatory drug).This medicine was developed listing in 1994 by Austrian Gebro-Broscheh Gmb H company first, China in 2002 in succession the kind of listing (S)-ibuprofen sheet, bolt, capsule etc. are arranged.As seen, substituting the raceme ibuprofen with (S)-ibuprofen is a kind of inexorable trend.
Levorotatory citirizine dihydrochloride is cetirizine hydrochloride R-isomer, and calendar year 2001, it was to H in German Initial Public Offering
1Affinity (the K of receptor
1=3.2nmol/L) be cetirizine (K
1=6.3nmol/L) twice is novel high selectivity periphery H
1Receptor antagonist.Compare with second filial generation antihistaminic, the curative effect advantage of this medicine is: 1. be unique chiral drug in the present antihistaminic that gone on the market; 2. as seen, this medicine onset time is the fastest in new antihistaminic by table 1; 3. be the antihistaminic that better to alleviate nasal congestion, improvement nasal obstruction symptom at present few in number.Ciprandi G, Cirilo I, Vizzaccaro A, et al.Levocetirizine improvesnasal obstruction and modulates cytokine pattern in patients with seasonal allergicrhinitis:a pilot study.Clin Exp Allergy, 2004,34:958-964 one literary composition compares levocetirizine to 30 routine pollinosis patients, the therapeutic effect of Desloratadine and placebo, show that preceding 2 kinds of medicines have kept the score the improvement except that total symptom, measure the nose throughput with rhinomanometer, only levocetirizine has improvement.Potter P C.Levocetirizine is effective for sym ptom relief including nasalcongestion in adolescent and adult (PAR) sensitized to house dust mites.Allergy, 2003,58:893-899 one literary composition is kept the score from symptom and is drawn levocetirizine group nasal obstruction symptom and also have 83% patient to improve.We can be intuitively as seen by accompanying drawing 1, and levocetirizine is especially more obvious than the Desloratadine effect alleviating nasal obstruction symptom side; 4. improve watery nasal discharge, rhinocnesmus, sneeze, shed tears, more lasting and remarkable than the effect of loratadine and terfenadine aspect the symptom such as cough.5. effective quick control allergic cough.6. have the important anti-inflammatory effect that is independent of the histamine blocking effect and stronger immunoregulatory activity.Compare with second filial generation antihistaminic, the security advantages of this medicine is: 1. by table 1 as seen, the distribution volume of this medicine value is minimum, and accumulating of liver and heart is few; 2. better tolerance, untoward reaction was few, applicable to 1 years old child.3. in the detection that patient's electrocardiogram is respectively led, do not find that this product had a significant effect to the QT interval.4. be different from loratadine and terfenadine, this medicine is discharged with prototype through kidney, need not liver metabolism, does not therefore have drug interaction with macrolide antibiotics such as liver drug enzyme inhibitor erythromycin, azithromycins.Because the situation of flu drug combination often exists, particularly treat the upper respiratory tract infection disease and often select macrolide antibiotics for use, so this medicine is the better selection that can use with Macrolide anti-infective safety compatibility.6. this medicine and glipizide do not have drug interaction, so this product is equally applicable to diabetes flu patient.As seen, it is feasible substituting traditional adrenomimetic drug class nasal congestion abirritant with levocetirizine dihydrochloride.
The representative new antihistaminic of table 1 and clinical relevant pharmacodynamics and pharmacokinetics characteristic
t
Max: oral back plasma drug level time to peak; t
1/2 β: do not get rid of eventually and partly dissociate the phase; A
T24: 24h is interior with the excretory total amount of former medicine form
The object of the present invention is to provide a kind of novel safely and effectively common cold treatment chiral composition, it is characterized in that containing (S)-ibuprofen (or its pharmaceutically acceptable salt) and levorotatory citirizine dihydrochloride.Because the half-life of levorotatory citirizine dihydrochloride is 7 ± 1.5h, persistent period is greater than 24h (seeing Table 1), the half-life of (S)-ibuprofen (or its pharmaceutically acceptable salt) only is 2 ± 0.5h, for making the synchronous synergetic effect better of two medicines, according to the clinical practice needs, part (S)-ibuprofen (or its pharmaceutically acceptable salt) is made slow-released part, and levorotatory citirizine dihydrochloride and surplus (S)-ibuprofen (or its pharmaceutically acceptable salt) are made immediate release section, form the oral slow release formulation of new compound jointly.Said composition can be worked in coordination with effects such as performance is analgesic, analgesia, alleviation nasal obstruction, watery nasal discharge, sneeze better, and curative effect is stronger, safety is better, the scope of application wider (comprising diabetics), obviously be better than traditional Buluoweima compound preparation, not seeing so far to have has identical research report both at home and abroad.
Chiral composition of the present invention, the pharmaceutically acceptable salt of wherein said (S)-ibuprofen comprise inorganic or organic base and (S)-ibuprofen salify.Suitable inorganic base comprises sodium, potassium, lithium, calcium, magnesium, aluminum, ferrum, zinc, copper, nickel and cobalt etc.; Suitable organic base comprises basic amino acid such as lysine, arginine, or organic amine such as cyclo-hexylamine, ethamine, pyridine, methylamino ethanol and piperazine etc., preferably the salt that makes of lysine or arginine and (S)-ibuprofen.Available conventional method prepares.Described levorotatory citirizine dihydrochloride is a levocetirizine dihydrochloride.
Chiral composition of the present invention, wherein said (S)-ibuprofen (or its pharmaceutically acceptable salt) and levocetirizine dihydrochloride all can be utilized conventional chemical synthesizing mean preparation well known by persons skilled in the art, also comprise and buy the raw material that meets standards of pharmacopoeia from the market.
Chiral composition of the present invention is characterized in that: the weight ratio of (S)-ibuprofen (or its pharmaceutically acceptable salt) and levocetirizine dihydrochloride is 50: 1～500: 1.
Chiral composition of the present invention is according to the preparation of galenic pharmacy routine techniques, and its preparation method comprises active component and the blended step of pharmaceutic adjuvant, makes the oral double-layer tablet dosage form of releasing slowly that is fit to take then.It is characterized in that, the double-layer tablet up and down that forms through twice compacting of bi-layer tablet press by pastille immediate-release granules and slow-releasing granules, wherein immediate release section is made up of acceptable rapid release adjuvant on the levocetirizine dihydrochloride of clinical effective and a certain proportion of (S)-ibuprofen (or its pharmaceutically acceptable salt) and the galenic pharmacy, can be in vivo after the medication disintegrate fast, absorbed by body rapidly and bring into play antipyretic effect fast and alleviate nasal obstruction, alleviate drug effects such as sneeze, watery nasal discharge, rhinocnesmus; Slow-released part is made up of acceptable slow-release auxiliary material on a certain proportion of (S)-ibuprofen (or its pharmaceutically acceptable salt) and the galenic pharmacy, wherein slow-release auxiliary material is can be by dissimilar and slow-release auxiliary material specification single or use by various combinations, can slowly discharge in vivo after the medication, long period is kept the interior blood drug level of body of (S)-ibuprofen (or its pharmaceutically acceptable salt), effects such as its antipyretic-antalgic of long-acting performance, thus cold symptoms alleviated comprehensively.
Chiral composition of the present invention is a unit dosage form, and these unit dosage forms can be pharmaceutical preparation unit dosage forms commonly used.For tablet, unit dose is meant every.With reference to clinical administration dosage, chiral composition of the present invention contains levocetirizine dihydrochloride 0.5-5mg, (S)-ibuprofen 50-800mg in the described oral unit dose of releasing double-layer tablet slowly; Be preferably levocetirizine dihydrochloride 1-3mg, (S)-ibuprofen 100-400mg most preferably is levocetirizine dihydrochloride 1.25mg, (S)-ibuprofen 200mg.Other are the medicine acceptable carrier.
Chiral composition of the present invention, the allocation proportion of described (S)-ibuprofen (or its pharmaceutically acceptable salt) gentle release system of rapid release in unit dose is 20%-40%: 60%-80%, be preferably 25%-35%: 65%-75% most preferably is 30%: 70%.
Chiral composition of the present invention, the described oral double-layer tablet dosage form of releasing slowly is characterized in that: except that principal agent, immediate release section and slow-released part can be chosen wantonly and comprise one or more and plant other acceptable accessories.These adjuvants are compositions of no therapeutical effect as known in the art, and they can be single or use by various combinations, comprise for example diluent, disintegrating agent, binding agent, fluidizer, lubricant, coloring agent, solubilizing agent and coating materials etc.Wherein diluent can be that lactose, starch, microcrystalline Cellulose, dextrin, amylum pregelatinisatum, mannitol, calcium carbonate, calcium hydrogen phosphate, calcium sulfate etc. are single or use by various combinations; Disintegrating agent can be that cross-linking sodium carboxymethyl cellulose, Sodium Hydroxymethyl Stalcs, microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, carboxymethyl starch sodium, polyvinylpolypyrrolidone etc. are single or use by various combinations; Binding agent can be that water, ethanol, gelatin, pregelatinized Starch, starch slurry, hydroxypropyl emthylcellulose, polyvinylpyrrolidone, polyvidone, Polyethylene Glycol, ethyl cellulose, acrylic resin etc. are single or use by various combinations; Fluidizer can be that silicon dioxide, Pulvis Talci etc. are single or use by various combinations; Lubricant can be that Pulvis Talci, magnesium stearate, zinc stearate, calcium stearate, stearic acid, micropowder silica gel, Polyethylene Glycol etc. are single or use by various combinations; Coloring agent can be food colorings such as sunset yellow aluminum color ingot.Solubilizing agent comprises surfactants such as dodecyl sodium sulfate or tween 80; Slow-released part can be chosen wantonly and comprise one or more and plant other pharmaceutically acceptable slow-release auxiliary material, the example gel framework material can be that the hydroxypropyl emthylcellulose of different viscosities is (as HPMC K4m, HPMCK15m, HPMC K100m etc.), sodium alginate, arabic gum, xanthan gum, chitosan etc.; Waxiness class framework material can be Brazil wax, waxiness 888, stearic acid, hexadecanol; The water-insoluble framework material can be methylcellulose (high molecular), hydroxyethyl-cellulose, ethyl cellulose; Can also be slow-release auxiliary material such as carbomer, acrylic resin, zein.Above slow-release auxiliary material is can be by dissimilar and slow-release auxiliary material specification single or use by various combinations.
The oral quick release slow releasing pharmaceutical dosage form of chiral composition of the present invention is characterized in that: except that principal agent, immediate release section contains following rapid release adjuvant:
1. suitable diluent, its amount is the 10%-70% of immediate release section weight;
2. suitable disintegrants, its amount is the 2%-10% of immediate release section weight;
3. suitable bonding, its amount is for an amount of;
4. suitable coloring agent, its amount is for an amount of;
5. suitable solubilizing agent: its amount is for an amount of;
6. suitable fluidizer, its amount is the heavy 0.5%-2% of immediate release section;
7. examples of suitable lubricants, its amount is the 0.5%-2% of immediate release section weight.
The oral quick release slow releasing pharmaceutical dosage form of chiral composition of the present invention is characterized in that: except that principal agent, slow-released part contains following slow-release auxiliary material:
1. suitable diluent, its amount is the 5%-35% of slow-released part weight;
2. suitable slow releasing agent, its amount is the heavy 5%-60% of slow-released part;
3. suitable bonding, its amount is for an amount of;
4. suitable coloring agent, its amount is for an amount of;
5. suitable solubilizing agent: its amount is for an amount of;
6. suitable fluidizer, its amount is the heavy 0.5%-2% of slow-released part;
7. examples of suitable lubricants, its amount is the 0.5%-2% of slow-released part weight.
Above-mentioned immediate release section suitable disintegrants is polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose or Sodium Hydroxymethyl Stalcs preferably; The suitable slow-release auxiliary material of slow-released part preferably hydroxypropyl emthylcellulose, ethyl cellulose is single or various combination is used.Rapid release and slow-released part the suitable diluent preferably single or various combination of lactose, microcrystalline Cellulose, calcium hydrogen phosphate or amylum pregelatinisatum are used; Suitable bonding is 2-8% polyvinylpyrrolidone alcoholic solution or 70%-95% alcoholic solution preferably; Suitable coloring agent is food coloring preferably; Suitable solubilizing agent is dodecyl sodium sulfate or tween 80 preferably; Suitable fluidizer is silica sol or Pulvis Talci preferably; Examples of suitable lubricants is magnesium stearate or zinc stearate preferably.
More than being meant in right amount according to the pharmaceutics routine techniques described in the prescription makes it reach the addition that preparation requires, and can add according to the requirement of textbook, is generally the 0.01%-5% of total weight, is preferably 0.1%-1%.
The oral double-layer tablet of releasing slowly of chiral composition of the present invention is characterized in that, the two-layer double-layer tablet up and down that pastille immediate-release granules and slow-releasing granules form through the bi-layer tablet press compacting, and hardness is 6-8kg/cm
2Two layers of this double-layer tablet can be white, also can be different colours.Every release layer is respectively become to be grouped into by following respectively with slow release layer:
| Release layer prescription (every consumption) | Preferably |
| (S)-ibuprofen | 10-320mg |
| Levocetirizine dihydrochloride | 0.5-5mg |
| Diluent | 5-350mg |
| Disintegrating agent | 1-50mg |
| Food coloring | In right amount |
| Solubilizing agent | In right amount |
| Binding agent | In right amount |
| Silicon dioxide | 0.25-10mg |
| Magnesium stearate | 0.25-10mg |
| Slow release layer prescription (every consumption) | |
| (S)-ibuprofen (or its pharmaceutically acceptable salt) | 30-640mg |
| Slow releasing agent | 2.5-300mg |
| Diluent | 2.5-175mg |
| Food coloring | In right amount |
| Solubilizing agent | In right amount |
| Binding agent | In right amount |
| Silicon dioxide | 0.25-10mg |
| Magnesium stearate | 0.25-10mg |
The most preferred prescription of the present invention is formed the process screening and is obtained, and has the slow controlled-release effect of best therapeutic effect and preparation, and most preferred prescription is listed in the embodiment of the invention.
Preparation method:
1. the preparation of immediate-release granules
Earlier raw and auxiliary material is crossed 80 mesh sieves respectively, take by weighing respectively again after recipe quantity (S)-ibuprofen (or its pharmaceutically acceptable salt), levocetirizine dihydrochloride and the adjuvant except that disintegrating agent, fluidizer and lubricant adopt equivalent to pass the interpretation of the law mix homogeneously, add binding agent and make soft material, after the granulation of 20 mesh sieves, wet granular is put 30 ℃ of vacuum dryings, and dried granule and disintegrating agent, magnesium stearate are always mixed, and crosses 18 mesh sieve granulate and gets immediate-release granules, measure 2 drug contents respectively, determine that layer is heavy.
2. the preparation of slow-releasing granules
80 mesh sieves will be crossed earlier behind the raw and auxiliary material mix homogeneously, take by weighing recipe quantity (S)-ibuprofen (or its pharmaceutically acceptable salt) and fluidizer and lubricant adjuvant in addition more respectively, after adopting equivalent to pass the interpretation of the law mix homogeneously, add the binding agent that contains food coloring and make soft material, after granulating with 20 mesh sieves, wet granular is put 30 ℃ of vacuum dryings, dried granule and magnesium stearate are always mixed, cross 18 mesh sieve granulate and get slow-releasing granules, measure drug content, determine that layer is heavy.
3. the preparation of double-layer tablet
Immediate-release granules is placed 1 loading hopper of the rotary bi-layer tablet press of ZPW23 (Tianxiang Jiantai Pharmaceutical Machinery Co., Ltd., Shanghai) earlier, elder generation is with less pressure precompressed and be adjusted to required first synusia heavily, again slow-releasing granules is placed in other 1 loading hopper of this bi-layer tablet press, pressurization and be adjusted to required total sheet heavy after, regulating slice, thin piece hardness is 6-8kg/cm
2After parameters such as the heavy and hardness of sheet were determined, start was suppressed continuously and is got final product.
4. coating
With double-layer tablet in coating pan with 5% Opadry according to the conventional formulation technology coatings.Because the fusing point of (S)-ibuprofen is 49～53 ℃, so leaving air temp is controlled at 30～35 ℃.
Following data declaration beneficial effect of the present invention by experiment:
Medicine with the preparation of the method for embodiment 1 has carried out following experiment, and the result is as follows:
The rapid release of double-layer tablet of the present invention and slow releasing function mainly by the release layer release, are brought into play the quick-acting effects of (S)-ibuprofen and levocetirizine dihydrochloride before the 1h; By the slow release layer release, bring into play the long-acting of (S)-ibuprofen behind the 1h.
One, the mensuration of (S)-ibuprofen release
1. release medium
(S)-ibuprofen is molten in the water part omitted.Double-layer tablet unit formulation specification of the present invention is preferably (S)-ibuprofen 200mg/ sheet, and the concentration of (S)-ibuprofen is 0.22mg/ml when selecting the complete stripping of 900ml release medium for use.With reference to pharmacopeia, when the phosphate buffer that adopts pH6.0 (is got potassium dihydrogen phosphate 68.05g, add 1mol/L sodium hydroxide solution 56ml, being diluted with water to 10000ml shakes up, pH value should be 6.0 ± 0.05) time, the saturated concentration of (S)-ibuprofen can reach 2mg/ml, can satisfy to discharge required sink conditions, so select for use the phosphate buffer of pH6.0 to do release medium.
2. detection wavelength determination
12.2mg (S)-ibuprofen (Sigma company provides) is dissolved in 10ml 50% methanol solution, scans in 200～400nm wave-length coverage, the result shows that (S)-ibuprofen has absorption maximum at 264nm wavelength place.Therefore the selected 264nm of double-layer tablet of the present invention is as the detection wavelength that detects the (S)-ibuprofen release.
3. chromatographic condition and system suitability test
Double-layer tablet of the present invention adopts the release of high effective liquid chromatography for measuring (S)-ibuprofen.The chromatographic condition of measuring is: chromatographic column is octadecylsilane chemically bonded silica post (Hypersil ODS C18 post 4.6mm * 150mm, 5 μ m); (acetonitrile 250ml mixes with 0.02mol/L potassium dihydrogen phosphate 250ml, adds dodecyl sodium sulfate 0.68g and makes dissolving, regulates pH value to 3.5 with phosphoric acid)-methanol (1: 1) is mobile phase with phosphate buffer; The detection wavelength is 263nm; Flow velocity 1.0ml/min; The column temperature room temperature; Sample size 20 μ l.Among the sample chromatogram figure, the theoretical cam curve of (S)-ibuprofen and separating degree all can reach requirement.
4. drug release determination method
Get double-layer tablet of the present invention and put in the special wire cage, to prevent this product come-up or to attach to sidewall or loom.Adopt Chinese Pharmacopoeia 2005 editions appendix XC dissolution method second subtraction unit (oar method), (get potassium dihydrogen phosphate 68.05g with phosphate buffer, add 1mol/L sodium hydroxide solution 56ml, being diluted with water to 10000ml shakes up, pH value should be 6.0 ± 0.05) 900ml is release medium, rotating speed is that per minute 30 changes, operation in accordance with the law, through 1 hour, 2 hours, 4 hours and 7 hours, respectively get solution 5ml, and replenish the release medium of uniform temp, equal volume simultaneously, filter, discard filtrate just, staying subsequent filtrate is test liquid.Chromatographic condition is: with octadecylsilane chemically bonded silica is filler; (acetonitrile 250ml mixes with 0.02mol/L potassium dihydrogen phosphate 250ml, adds dodecyl sodium sulfate 0.68g and makes dissolving, regulates pH value to 3.5 with phosphoric acid)-methanol (1: 1) is mobile phase with phosphate buffer; The detection wavelength is 263nm; Number of theoretical plate calculates by the (S)-ibuprofen honeybee and is not less than 3000.Precision is measured subsequent filtrate 20 μ l, injects chromatograph of liquid, the record chromatogram; It is an amount of that other gets the (S)-ibuprofen reference substance, and precision claims fixed, adds the also quantitative dilution of release medium dissolving and make the solution that contains 300 μ g among every 1ml approximately, measures with method.Calculate every burst size respectively, calculate total release percentage, draw accumulative total release profiles (seeing Table 2) at different time.Every of this product should be respectively more than 37%～54.5%, 47.5%～68.5%, 65%～86% and 82.5% of sign amount 1 hour, 2 hours, the 4 hours burst sizes during with 7 hours, all should be up to specification.
Table 2 (S)-ibuprofen release tables of data
With each sheet accumulative total release the time is mapped, get (S)-ibuprofen release homogeneity curve chart (seeing accompanying drawing 2), visible double-layer tablet preparation process of the present invention is stable, and it is better that (S)-ibuprofen discharges homogeneity; With average release the time is mapped, the (S)-ibuprofen cumulative release line chart (seeing accompanying drawing 3) of writing music, by the mathematical model fitting method releasing mechanism of (S)-ibuprofen has been carried out preliminary discussion, the result shows that (S)-ibuprofen discharges Higuchi equation Q=19.246t
1/2+ 31.876 R
2=0.9742 and one-level discharge equation ln (100-Q)=-0.2217+4.1704 R
2=0.9745; Release mechanism is diffusion and corrosion synergism, and based on flooding mechanism.
Two, levocetirizine dihydrochloride determination of dissolution rate
1. dissolution medium
Levocetirizine dihydrochloride is easily molten in water.Double-layer tablet unit formulation specification of the present invention is preferably levocetirizine dihydrochloride 1.25mg/ sheet, according to 2005 editions appendix XC of Chinese Pharmacopoeia dissolution method three therapeutic methods of traditional Chinese medicine, the concentration of levocetirizine dihydrochloride is 0.005mg/ml when selecting the complete stripping of 250ml release medium for use, so select for use distilled water to do dissolution medium, can satisfy the required sink conditions of stripping
2. detection wavelength determination
(Nat'l Pharmaceutical ﹠ Biological Products Control Institute provides the 20mg levocetirizine dihydrochloride, lot number 10261-0101) is dissolved in the 10ml distilled water solution, scan in 200～400nm wave-length coverage, the result shows that levocetirizine dihydrochloride has absorption maximum at 230nm wavelength place.Therefore the selected 230nm of double-layer tablet of the present invention is as the detection wavelength that detects the levocetirizine dihydrochloride dissolution.
3. chromatographic condition and system suitability test
Double-layer tablet of the present invention adopts the dissolution of high effective liquid chromatography for measuring levocetirizine dihydrochloride.The chromatographic condition of measuring is: chromatographic column is octadecylsilane chemically bonded silica post (Hypersil ODS C18 post 4.6mm * 150mm, 5 μ m); (get NaH with methanol-0.02mol/L sodium dihydrogen phosphate
2PO
4.2H
2O 3.12g adds water to 1000ml dissolving) (75: 25) be mobile phase; The detection wavelength is 230nm; Flow velocity 1.0ml/min; The column temperature room temperature; Sample size 20 μ l.Among the sample chromatogram figure, levocetirizine dihydrochloride theoretical cam curve and separating degree all can reach requirement.
4. dissolution determination method
Get double-layer tablet of the present invention and put in the special wire cage, to prevent this product come-up or to attach to sidewall or loom.Adopt Chinese Pharmacopoeia 2005 editions appendix XC dissolution method the 3rd subtraction unit (oar method), 250ml is a dissolution medium with degassing distilled water, and rotating speed is that per minute 50 changes, operation in accordance with the law, respectively get solution 5ml through 45min and filter, discard filtrate just, staying subsequent filtrate is test liquid.Chromatographic condition is: with octadecylsilane chemically bonded silica is filler; (get NaH with methanol-0.02mol/L sodium dihydrogen phosphate
2PO
4.2H
2O 3.12g adds water to 1000ml dissolving) (75: 25) be mobile phase; The detection wavelength is 230nm; Number of theoretical plate calculates by the levocetirizine dihydrochloride peak and is not less than 2000.Precision is measured filtrate 20 μ l, injects chromatograph of liquid, the record chromatogram; It is an amount of that other gets the levocetirizine dihydrochloride reference substance, and accurate the title decides, and adds the also quantitative dilution of stripping medium dissolves and make the solution that contains 5 μ g among every 1ml approximately, measures with method.Calculate every burst size respectively, calculate accumulative total stripping percentage rate (seeing Table 3), draw stripping homogeneity curve (seeing accompanying drawing 3) at different time.Every dissolution at 45min of this product should be more than 75% of sign amount, all should be up to specification.
Table 3 levocetirizine dihydrochloride dissolution data table
By table 3 and accompanying drawing 4 as can be known, each the sheet dissolution and the homogeneity of levocetirizine dihydrochloride are all qualified, meet the quality standard requirement.
Double-layer tablet of the present invention is through above release in vitro degree and dissolution test shows, it has that ordinary preparation proves effective soon, slow releasing preparation lasting medicine, stable advantage, can reach the immediate release section medicine fully discharges rapidly in vivo, after reaching effective blood drug concentration fast, slow-released part slowly discharges again, and continues to keep effective blood drug concentration.
Double-layer tablet of the present invention is made a bet through rabbit and is shot dead escherichia coli culture fluid method to death, rabbit vein is injected animal pharmacodynamics evidences such as Typhoid-Paratyphoid first, second triple vaccine method, rabbit vein injection Bacillus typhi endotoxin method, mice hot plate method, mouse writhing method, Cavia porcellus allergic rhinitis, (S)-ibuprofen and levocetirizine dihydrochloride compatibility, can work in coordination with effects such as performance is analgesic, analgesia, alleviation nasal obstruction, watery nasal discharge, sneeze, and curative effect is stronger than single drug, and untoward reaction is less.
Description of drawings
Fig. 1 LEVO CITRAZINE (levocetirizine) and Desloratadine (desloratadine) compare the drug effect of symptoms such as sneeze, rhinocnesmus, watery nasal discharge, nasal obstruction
Fig. 2 (S)-ibuprofen accumulative total release homogeneity curve
The average cumulative release curve of Fig. 3 (S)-ibuprofen
Fig. 4 LEVO CITRAZINE stripping homogeneity curve
The specific embodiment
The present invention is further illustrated below in conjunction with embodiment, but be not any limitation of the invention.
Compound recipe (S)-ibuprofen/levocetirizine dihydrochloride double-layer tablet (be administered once in per 12 hours, and once obeyed 2)
Prescription (1000)
| The release layer prescription | |
| (S)-ibuprofen | 60g |
| Levocetirizine dihydrochloride | 1.25g |
| Lactose | 59.75g |
| Microcrystalline Cellulose | 40g |
| Amylum pregelatinisatum | 25g |
| Polyvinylpolypyrrolidone | 12g |
| 8% 30 POVIDONE K 30 BP/USP, 3095% alcoholic solution | In right amount |
| Silicon dioxide | 1g |
| Magnesium stearate | 1g |
| The slow release layer prescription | |
| (S)-ibuprofen (or its pharmaceutically acceptable salt) | 140g |
| Hydroxypropyl emthylcellulose K100m | 12.5g |
| Hydroxypropyl emthylcellulose K4m | 12.5g |
| The release layer prescription | |
| Lactose | 45g |
| Microcrystalline Cellulose | 20g |
| Amylum pregelatinisatum | 18g |
| Food coloring (as sunset yellow aluminum color ingot etc.) | In |
| 8% polyvinylpyrrolidone, 70% alcoholic solution | In right amount |
| Silicon dioxide | 1g |
| Magnesium stearate | 1g |
Preparation method: earlier raw and auxiliary material is crossed 80 mesh sieves respectively, take by weighing recipe quantity (S)-ibuprofen (or its pharmaceutically acceptable salt), levocetirizine dihydrochloride, lactose, starch and microcrystalline Cellulose more respectively, after adopting equivalent to pass the interpretation of the law mix homogeneously, add an amount of 8% 30 POVIDONE K 30 BP/USP, 3095% alcoholic solution and make soft material, after the granulation of 20 mesh sieves, wet granular is put 30 ℃ of vacuum dryings, dried granule and polyvinylpolypyrrolidone, silicon dioxide, magnesium stearate are always mixed, cross 18 mesh sieve granulate and get immediate-release granules, survey drug content, it is heavy to calculate the rapid release synusia.
80 mesh sieves will be crossed earlier behind the raw and auxiliary material mix homogeneously, take by weighing recipe quantity (S)-ibuprofen (or its pharmaceutically acceptable salt), HPMC K100m, HPMC K4m, lactose, microcrystalline Cellulose and amylum pregelatinisatum more respectively, after adopting equivalent to pass the interpretation of the law mix homogeneously, add 8% polyvinylpyrrolidone, 70% alcoholic solution that contains sunset yellow aluminum color ingot in right amount and make soft material, after the granulation of 20 mesh sieves, wet granular is put 30 ℃ of vacuum dryings, dried granule and silicon dioxide, magnesium stearate are always mixed, cross 18 mesh sieve granulate, survey drug content, it is heavy to calculate the slow release synusia.
Adopt the bi-layer tablet press compacting to form, hardness is about 6-8kg/cm
2
Compound recipe (S)-ibuprofen/levocetirizine dihydrochloride bilayer tablet (be administered once in per 12 hours, and once obeyed 2)
Prescription (1000)
| The release layer prescription | |
| (S)-ibuprofen | 70g |
| Levocetirizine dihydrochloride | 1.25g |
| Lactose | 49.75g |
| Microcrystalline Cellulose | 40g |
| The release layer prescription | |
| Amylum pregelatinisatum | 25g |
| Cross-linking sodium carboxymethyl cellulose | 12g |
| Silicon dioxide | 1g |
| Magnesium stearate | 1g |
| The slow release layer prescription | |
| (S)-ibuprofen (or its pharmaceutically acceptable salt) | 130g |
| Hydroxypropyl emthylcellulose K15m | 25g |
| Ethyl cellulose | 25g |
| Lactose | 30g |
| Microcrystalline Cellulose | 20g |
| Amylum pregelatinisatum | 18g |
| Food coloring (as sunset yellow aluminum color ingot etc.) | In |
| 8% polyvinylpyrrolidone, 80% alcoholic solution | In right amount |
| Silicon dioxide | 1g |
| Magnesium stearate | 1g |
Preparation method: earlier raw and auxiliary material is crossed 80 mesh sieves respectively, take by weighing recipe quantity (S)-ibuprofen (or its pharmaceutically acceptable salt), levocetirizine dihydrochloride, lactose, starch, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, silicon dioxide and magnesium stearate more respectively, adopt equivalent to pass the interpretation of the law mix homogeneously, cross 18 mesh sieve granulate and get immediate-release granules, survey drug content, it is heavy to calculate the rapid release synusia.
80 mesh sieves will be crossed earlier behind the raw and auxiliary material mix homogeneously, take by weighing recipe quantity (S)-ibuprofen (or its pharmaceutically acceptable salt), HPMC K15m, ethyl cellulose, lactose, microcrystalline Cellulose and amylum pregelatinisatum more respectively, after adopting equivalent to pass the interpretation of the law mix homogeneously, add 8% polyvinylpyrrolidone, 80% alcoholic solution that contains sunset yellow aluminum color ingot in right amount and make soft material, after the granulation of 20 mesh sieves, wet granular is put 30 ℃ of vacuum dryings, dried granule and silicon dioxide, magnesium stearate are always mixed, cross 18 mesh sieve granulate, survey drug content, it is heavy to calculate the slow release synusia.
Adopt the bi-layer tablet press compacting to form, hardness is about 6-8kg/cm
2
Compound recipe (S)-ibuprofen/levocetirizine dihydrochloride double-layer tablet (be administered once in per 12 hours, and once obeyed 2)
Prescription (1000)
| The release layer prescription | |
| (S)-ibuprofen | 50g |
| Levocetirizine dihydrochloride | 1.25g |
| Lactose | 69.75g |
| Microcrystalline Cellulose | 40g |
| Amylum pregelatinisatum | 25g |
| Sodium Hydroxymethyl Stalcs | 12g |
| 95% ethanol | In right amount |
| Silicon dioxide | 1g |
| Magnesium stearate | 1g |
| The slow release layer prescription | |
| (S)-ibuprofen (or its pharmaceutically acceptable salt) | 150g |
| Hydroxypropyl emthylcellulose K100m | 20g |
| Lactose | 40g |
| Microcrystalline Cellulose | 20g |
| Amylum pregelatinisatum | 18g |
| Food coloring (as sunset yellow aluminum color ingot etc.) | In |
| 8% polyvinylpyrrolidone, 75% alcoholic solution | In right amount |
| Silicon dioxide | 1g |
| Magnesium stearate | 1g |
Preparation method: earlier raw and auxiliary material is crossed 80 mesh sieves respectively, take by weighing recipe quantity levocetirizine dihydrochloride, lactose, starch and microcrystalline Cellulose, after adopting equivalent to pass the interpretation of the law mix homogeneously, add an amount of 95% alcoholic solution and make soft material, after the granulation of 20 mesh sieves, wet granular is put 30 ℃ of vacuum dryings, dried granule and recipe quantity (S)-ibuprofen (or its pharmaceutically acceptable salt), crosslinked Sodium Hydroxymethyl Stalcs, silicon dioxide, magnesium stearate are always mixed, cross 18 mesh sieve granulate and get immediate-release granules, survey drug content, it is heavy to calculate the rapid release synusia.
80 mesh sieves will be crossed earlier behind the raw and auxiliary material mix homogeneously, take by weighing recipe quantity (S)-ibuprofen (or its pharmaceutically acceptable salt), HPMC K100m, lactose, microcrystalline Cellulose and amylum pregelatinisatum more respectively, after adopting equivalent to pass the interpretation of the law mix homogeneously, add 8% polyvinylpyrrolidone, 75% alcoholic solution that contains sunset yellow aluminum color ingot in right amount and make soft material, after the granulation of 20 mesh sieves, wet granular is put 30 ℃ of vacuum dryings, dried granule and silicon dioxide, magnesium stearate are always mixed, cross 18 mesh sieve granulate, survey drug content, it is heavy to calculate the slow release synusia.
Adopt the bi-layer tablet press compacting to form, hardness is about 6-8kg/cm
2
Compound recipe (S)-ibuprofen/levocetirizine dihydrochloride bilayer tablet (be administered once in per 12 hours, and once obeyed 2)
Prescription (1000)
| The release layer prescription | |
| (S)-ibuprofen | 60g |
| Levocetirizine dihydrochloride | 1.25g |
| Lactose | 59.75g |
| Microcrystalline Cellulose | 40g |
| Amylum pregelatinisatum | 25g |
| Polyvinylpolypyrrolidone | 12g |
| 8% 30 POVIDONE K 30 BP/USP, 3095% alcoholic solution | In right amount |
| Silicon dioxide | 1g |
| Magnesium stearate | 1g |
| The slow release layer prescription | |
| (S)-ibuprofen (or its pharmaceutically acceptable salt) | 140g |
| Hydroxypropyl emthylcellulose K4m | 75g |
| Calcium hydrogen phosphate | 15g |
| Amylum pregelatinisatum | 18g |
| The release layer prescription | |
| Food coloring (as sunset yellow aluminum color ingot etc.) | In |
| Tween | |
| 80 | In |
| 8% polyvinylpyrrolidone, 80% alcoholic solution | In right amount |
| Silicon dioxide | 1g |
| Magnesium stearate | 1g |
Preparation method: earlier raw and auxiliary material is crossed 80 mesh sieves respectively, take by weighing recipe quantity (S)-ibuprofen (or its pharmaceutically acceptable salt), levocetirizine dihydrochloride, lactose, starch and microcrystalline Cellulose more respectively, after adopting equivalent to pass the interpretation of the law mix homogeneously, add an amount of 8% 30 POVIDONE K 30 BP/USP, 3095% alcoholic solution and make soft material, after the granulation of 20 mesh sieves, wet granular is put 30 ℃ of vacuum dryings, dried granule and polyvinylpolypyrrolidone, silicon dioxide, magnesium stearate are always mixed, cross 18 mesh sieve granulate and get immediate-release granules, survey drug content, it is heavy to calculate the rapid release synusia.
80 mesh sieves will be crossed earlier behind the raw and auxiliary material mix homogeneously, take by weighing recipe quantity (S)-ibuprofen (or its pharmaceutically acceptable salt), HPMC K4m, calcium hydrogen phosphate and amylum pregelatinisatum more respectively, after adopting equivalent to pass the interpretation of the law mix homogeneously, add 8% polyvinylpyrrolidone, 80% alcoholic solution that contains sunset yellow aluminum color ingot and tween 80 in right amount and make soft material, after the granulation of 20 mesh sieves, wet granular is put 30 ℃ of vacuum dryings, dried granule and silicon dioxide, magnesium stearate are always mixed, cross 18 mesh sieve granulate, survey drug content, it is heavy to calculate the slow release synusia.
Adopt the bi-layer tablet press compacting to form, hardness is about 6-8kg/cm
2
Compound recipe (S)-ibuprofen/levocetirizine dihydrochloride double-layer tablet (be administered once in per 12 hours, and once obeyed 1)
Prescription (1000)
| The release layer prescription | |
| (S)-ibuprofen | 120g |
| Levocetirizine dihydrochloride | 2.5g |
| Lactose | 119.5g |
| Microcrystalline Cellulose | 80g |
| Amylum pregelatinisatum | 50g |
| Polyvinylpolypyrrolidone | 24g |
| The release layer prescription | |
| 95% alcoholic solution | In right amount |
| Silicon dioxide | 2g |
| Magnesium stearate | 2g |
| The slow release layer prescription | |
| (S)-ibuprofen (or its pharmaceutically acceptable salt) | 280g |
| Hydroxypropyl emthylcellulose K15m | 30g |
| Hydroxypropyl emthylcellulose K4m | 40g |
| Lactose | 60g |
| Calcium hydrogen phosphate | 50g |
| Amylum pregelatinisatum | 36g |
| Food coloring (as sunset yellow aluminum color ingot etc.) | In |
| 8% polyvinylpyrrolidone, 70% alcoholic solution | In right amount |
| Silicon dioxide | 2g |
| Magnesium stearate | 2g |
Preparation method: earlier raw and auxiliary material is crossed 80 mesh sieves respectively, take by weighing recipe quantity levocetirizine dihydrochloride, lactose, starch and microcrystalline Cellulose, after adopting equivalent to pass the interpretation of the law mix homogeneously, add an amount of 95% alcoholic solution and make soft material, after the granulation of 20 mesh sieves, wet granular is put 30 ℃ of vacuum dryings, dried granule and recipe quantity (S)-ibuprofen (or its pharmaceutically acceptable salt), polyvinylpolypyrrolidone, silicon dioxide, magnesium stearate are always mixed, cross 18 mesh sieve granulate and get immediate-release granules, survey drug content, it is heavy to calculate the rapid release synusia.
80 mesh sieves will be crossed earlier behind the raw and auxiliary material mix homogeneously, take by weighing recipe quantity (S)-ibuprofen (or its pharmaceutically acceptable salt), HPMC K15m, HPMC K4m, lactose, calcium hydrogen phosphate and amylum pregelatinisatum more respectively, after adopting equivalent to pass the interpretation of the law mix homogeneously, add 8% polyvinylpyrrolidone, 70% alcoholic solution that contains sunset yellow aluminum color ingot in right amount and make soft material, after the granulation of 20 mesh sieves, wet granular is put 30 ℃ of vacuum dryings, dried granule and silicon dioxide, magnesium stearate are always mixed, cross 18 mesh sieve granulate, survey drug content, it is heavy to calculate the slow release synusia.
Adopt the bi-layer tablet press compacting to form, hardness is about 6-8kg/cm
2
Compound recipe (S)-ibuprofen/levocetirizine dihydrochloride double-layer tablet (be administered once in per 24 hours, and once obeyed 2)
Prescription (1000)
| The release layer prescription | |
| (S)-ibuprofen | 120g |
| Levocetirizine dihydrochloride | 2.5g |
| Lactose | 119.5g |
| Microcrystalline Cellulose | 123g |
| Amylum pregelatinisatum | 100g |
| Polyvinylpolypyrrolidone | 30g |
| 5% 30 POVIDONE K 30 BP/USP, 3095% alcoholic solution | In right amount |
| Silicon dioxide | 2.5g |
| Magnesium stearate | 2.5g |
| The slow release layer prescription | |
| (S)-ibuprofen (or its pharmaceutically acceptable salt) | 280g |
| Hydroxypropyl emthylcellulose K4m | 100g |
| Ethyl cellulose | 50g |
| Lactose | 40g |
| Calcium hydrogen phosphate | 20g |
| Amylum pregelatinisatum | 6g |
| Food coloring (as sunset yellow aluminum color ingot etc.) | In |
| 8% polyvinylpyrrolidone, 80% alcoholic solution | In right amount |
| Silicon dioxide | 2g |
| Magnesium stearate | 2g |
Preparation method: earlier raw and auxiliary material is crossed 80 mesh sieves respectively, take by weighing recipe quantity (S)-ibuprofen (or its pharmaceutically acceptable salt), levocetirizine dihydrochloride, lactose, starch and microcrystalline Cellulose more respectively, after adopting equivalent to pass the interpretation of the law mix homogeneously, add an amount of 5% 30 POVIDONE K 30 BP/USP, 3095% alcoholic solution and make soft material, after the granulation of 20 mesh sieves, wet granular is put 30 ℃ of vacuum dryings, dried granule and polyvinylpolypyrrolidone, silicon dioxide, magnesium stearate are always mixed, cross 18 mesh sieve granulate and get immediate-release granules, survey drug content, it is heavy to calculate the rapid release synusia.
80 mesh sieves will be crossed earlier behind the raw and auxiliary material mix homogeneously, take by weighing recipe quantity (S)-ibuprofen (or its pharmaceutically acceptable salt), HPMC K4m, ethyl cellulose, lactose, calcium hydrogen phosphate and amylum pregelatinisatum more respectively, after adopting equivalent to pass the interpretation of the law mix homogeneously, add 5% polyvinylpyrrolidone, 80% alcoholic solution that contains sunset yellow aluminum color ingot in right amount and make soft material, after the granulation of 20 mesh sieves, wet granular is put 30 ℃ of vacuum dryings, dried granule and silicon dioxide, magnesium stearate are always mixed, cross 18 mesh sieve granulate, survey drug content, it is heavy to calculate the slow release synusia.
Adopt the bi-layer tablet press compacting to form, hardness is about 6-8kg/cm
2
Claims (2)
1. double-layer tablet pharmaceutical composition for the treatment of flu, be is characterized in that through the double-layer tablet up and down that twice compacting of bi-layer tablet press forms by pastille immediate-release granules and slow-releasing granules, its release layer and slow release layer respectively by following each become to be grouped into:
Release layer: every consumption
(S)-ibuprofen 10-320mg
Levocetirizine dihydrochloride 0.5-5mg
Diluent 5-350mg
Disintegrating agent 1-50mg
Food coloring is an amount of
Solubilizing agent is an amount of
Binding agent is an amount of
Silicon dioxide 0.25-10mg
Magnesium stearate 0.25-10mg
Slow release layer: every consumption
(S)-ibuprofen or its pharmaceutically acceptable salt 30-640mg
Slow releasing agent 2.5-300mg
Diluent 2.5-175mg
Food coloring is an amount of
Solubilizing agent is an amount of
Binding agent is an amount of
Silicon dioxide 0.25-10mg
Magnesium stearate 0.25-10mg
Wherein said disintegrating agent is selected from polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose or Sodium Hydroxymethyl Stalcs; Described slow releasing agent is selected from hydroxypropyl emthylcellulose, ethyl cellulose; Described diluent is selected from lactose, microcrystalline Cellulose, calcium hydrogen phosphate or amylum pregelatinisatum; Described binding agent is selected from 2-8% polyvinylpyrrolidone alcoholic solution or 70%-95% alcoholic solution; Solubilizing agent is selected from dodecyl sodium sulfate or tween 80.
2. according to the double-layer tablet pharmaceutical composition of claim 1, it is characterized in that its release layer is respectively become to be grouped into by following respectively with slow release layer:
Release layer: per 1000 consumptions
(S)-ibuprofen 60g
Levocetirizine dihydrochloride 1.25g
Lactose 59.75g
Microcrystalline Cellulose 40g
Amylum pregelatinisatum 25g
Polyvinylpolypyrrolidone 12g
8% 30 POVIDONE K 30 BP/USP, 3095% alcoholic solution is an amount of
Silica 1 g
Magnesium stearate 1g
Slow release layer:
(S)-ibuprofen or its pharmaceutically acceptable salt 140g
Hydroxypropyl emthylcellulose K4m 75g
Calcium hydrogen phosphate 15g
Amylum pregelatinisatum 18g
Food coloring is an amount of
Tween 80 is an amount of
8% polyvinylpyrrolidone, 80% alcoholic solution is an amount of
Silica 1 g
Magnesium stearate 1g.
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| CN2007100033931A CN101073563B (en) | 2007-02-07 | 2007-02-07 | Chiral composition containing dextrothyroxine buprofenli and levomethadyl cysteliqin and its double slow-releasing tablet |
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| CN2007100033931A CN101073563B (en) | 2007-02-07 | 2007-02-07 | Chiral composition containing dextrothyroxine buprofenli and levomethadyl cysteliqin and its double slow-releasing tablet |
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| CN101073563B true CN101073563B (en) | 2010-10-06 |
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| CN101744786B (en) * | 2008-12-17 | 2012-11-14 | 南京星银药业集团有限公司 | Prescription of felodipine sustained-release tablets and preparation method |
| CN102008726A (en) * | 2010-11-05 | 2011-04-13 | 航天中心医院 | Dexiburofen amino acid salt-containing medicament for colds |
| CN102058564B (en) * | 2010-12-29 | 2013-03-06 | 成都师创生物医药科技有限公司 | Zaltoprofen slow-release/controlled-release preparation and preparation method thereof |
| CN102160855B (en) * | 2011-03-30 | 2013-01-23 | 吴家安 | Dex-ibuprofen sustained release tablets and preparation method thereof |
| KR20130009553A (en) * | 2011-07-15 | 2013-01-23 | 한미약품 주식회사 | Capsule formulation comprising montelukast or a pharmaceutically acceptable salt thereof, and levocetirizine or a pharmaceutically acceptable salt thereof |
| CN102258519A (en) * | 2011-08-19 | 2011-11-30 | 西安利君制药有限责任公司 | Application of dexibuprofen levocetrizine sustained release bilayer tablet in treating airway inflammation |
| CN102716099B (en) * | 2012-07-05 | 2013-10-09 | 湖南千金湘江药业股份有限公司 | Levocetirizine hydrochloride chewable tablet and preparation method thereof |
| CN104546732A (en) * | 2013-10-24 | 2015-04-29 | 北京韩美药品有限公司 | Dexibuprofen sustained-release tablet and preparation process thereof |
| CN107007564A (en) * | 2017-04-12 | 2017-08-04 | 南京康川济医药科技有限公司 | A kind of medicinal composition of the double-layer sustained release containing brufen and PHENYLEPHRINE HYDROCHLORIDE and preparation method thereof |
| CN106943388A (en) * | 2017-04-21 | 2017-07-14 | 南京康川济医药科技有限公司 | A kind of double-deck Pharmaceutical composition containing brufen and PHENYLEPHRINE HYDROCHLORIDE and preparation method thereof |
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| 游运辉等.右旋布洛芬栓剂的II期临床研究.中南大学学报(医学版)29 4.2004,29(4),457-459. * |
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