CN104586812A - Composition containing linezolid as well as preparation method thereof - Google Patents
Composition containing linezolid as well as preparation method thereof Download PDFInfo
- Publication number
- CN104586812A CN104586812A CN201410821559.0A CN201410821559A CN104586812A CN 104586812 A CN104586812 A CN 104586812A CN 201410821559 A CN201410821559 A CN 201410821559A CN 104586812 A CN104586812 A CN 104586812A
- Authority
- CN
- China
- Prior art keywords
- linezolid
- citric acid
- sodium bicarbonate
- anhydrous citric
- extra section
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- TYZROVQLWOKYKF-ZDUSSCGKSA-N linezolid Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C(C=C1F)=CC=C1N1CCOCC1 TYZROVQLWOKYKF-ZDUSSCGKSA-N 0.000 title claims abstract description 60
- 229960003907 linezolid Drugs 0.000 title claims abstract description 52
- 239000000203 mixture Substances 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims abstract description 61
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims abstract description 40
- 229960004543 anhydrous citric acid Drugs 0.000 claims abstract description 29
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims abstract description 22
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 20
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims abstract description 20
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims abstract description 20
- 235000017557 sodium bicarbonate Nutrition 0.000 claims abstract description 20
- 238000000034 method Methods 0.000 claims abstract description 18
- 229960000913 crospovidone Drugs 0.000 claims abstract description 16
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims abstract description 16
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims abstract description 16
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims abstract description 10
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims abstract description 10
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims abstract description 10
- 229920002472 Starch Polymers 0.000 claims abstract description 10
- 239000008101 lactose Substances 0.000 claims abstract description 10
- 235000019359 magnesium stearate Nutrition 0.000 claims abstract description 10
- 239000000377 silicon dioxide Substances 0.000 claims abstract description 10
- 235000012239 silicon dioxide Nutrition 0.000 claims abstract description 10
- 235000019333 sodium laurylsulphate Nutrition 0.000 claims abstract description 10
- 235000019698 starch Nutrition 0.000 claims abstract description 10
- 239000008107 starch Substances 0.000 claims abstract description 10
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims abstract description 6
- 239000013078 crystal Substances 0.000 claims description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- 230000015572 biosynthetic process Effects 0.000 claims description 11
- 238000000576 coating method Methods 0.000 claims description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- 239000011248 coating agent Substances 0.000 claims description 10
- 239000004141 Sodium laurylsulphate Substances 0.000 claims description 9
- 239000010410 layer Substances 0.000 claims description 7
- 229920003072 Plasdone™ povidone Polymers 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 6
- 230000004584 weight gain Effects 0.000 claims description 6
- 235000019786 weight gain Nutrition 0.000 claims description 6
- 239000001856 Ethyl cellulose Substances 0.000 claims description 3
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims description 3
- 230000001476 alcoholic effect Effects 0.000 claims description 3
- 230000004888 barrier function Effects 0.000 claims description 3
- 238000007796 conventional method Methods 0.000 claims description 3
- 229920001249 ethyl cellulose Polymers 0.000 claims description 3
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 3
- 239000008187 granular material Substances 0.000 claims description 3
- 239000011247 coating layer Substances 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 abstract description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 abstract description 3
- 229920001531 copovidone Polymers 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- 229960001375 lactose Drugs 0.000 abstract 1
- 229940057948 magnesium stearate Drugs 0.000 abstract 1
- 229960001866 silicon dioxide Drugs 0.000 abstract 1
- 238000004090 dissolution Methods 0.000 description 20
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 15
- 230000000694 effects Effects 0.000 description 8
- 239000000463 material Substances 0.000 description 8
- 239000003814 drug Substances 0.000 description 7
- 238000004519 manufacturing process Methods 0.000 description 7
- 230000000844 anti-bacterial effect Effects 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 5
- 206010059866 Drug resistance Diseases 0.000 description 4
- 239000008351 acetate buffer Substances 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 230000008676 import Effects 0.000 description 4
- 239000008363 phosphate buffer Substances 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 239000008213 purified water Substances 0.000 description 4
- 241000194033 Enterococcus Species 0.000 description 3
- 206010035664 Pneumonia Diseases 0.000 description 3
- 239000002671 adjuvant Substances 0.000 description 3
- 230000002950 deficient Effects 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 2
- 206010062255 Soft tissue infection Diseases 0.000 description 2
- 241000193998 Streptococcus pneumoniae Species 0.000 description 2
- 241000193996 Streptococcus pyogenes Species 0.000 description 2
- 108010059993 Vancomycin Proteins 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 230000007812 deficiency Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000004811 liquid chromatography Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 238000009702 powder compression Methods 0.000 description 2
- 210000004708 ribosome subunit Anatomy 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 229940031000 streptococcus pneumoniae Drugs 0.000 description 2
- 229960003165 vancomycin Drugs 0.000 description 2
- MYPYJXKWCTUITO-LYRMYLQWSA-N vancomycin Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-N 0.000 description 2
- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 description 2
- 238000005550 wet granulation Methods 0.000 description 2
- UYGKMSUDBLULNG-UHFFFAOYSA-N 3-[(2-oxo-1,3-oxazolidin-5-yl)methyl]thiophene-2-carboxamide Chemical class S1C=CC(CC2OC(=O)NC2)=C1C(=O)N UYGKMSUDBLULNG-UHFFFAOYSA-N 0.000 description 1
- 229920000742 Cotton Polymers 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 208000008745 Healthcare-Associated Pneumonia Diseases 0.000 description 1
- 241000588621 Moraxella Species 0.000 description 1
- 108090000279 Peptidyltransferases Proteins 0.000 description 1
- 108050001408 Profilin Proteins 0.000 description 1
- 102000011195 Profilin Human genes 0.000 description 1
- 206010041925 Staphylococcal infections Diseases 0.000 description 1
- 241000191940 Staphylococcus Species 0.000 description 1
- 241000191963 Staphylococcus epidermidis Species 0.000 description 1
- 241000194017 Streptococcus Species 0.000 description 1
- 241000193985 Streptococcus agalactiae Species 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 230000002730 additional effect Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 229960004106 citric acid Drugs 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 238000007908 dry granulation Methods 0.000 description 1
- 239000000428 dust Substances 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000005187 foaming Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 230000002949 hemolytic effect Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 206010022000 influenza Diseases 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 208000015688 methicillin-resistant staphylococcus aureus infectious disease Diseases 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 229940076156 streptococcus pyogenes Drugs 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000012622 synthetic inhibitor Substances 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
Abstract
The invention relates to a composition containing linezolid. The compositoion consists of linezolid, sodium lauryl sulfate, copovidone, starch lactose, crospovidone, anhydrous citric acid, sodium bicarbonate, magnesium stearate and silicon dioxide. The invention further discloses a method for preparing the composition containing linezolid. The problems that linezolid is poor in solubility and the like are solved by adopting dry granulating, adding anhydrous citric acid and sodium bicarbonate as an effervescing agent, controlling the proportion of internal addition and external addition and the like. The composition containing linezolid is particularly stable in quality and good in solubility, so that the product quality is greatly improved. The preparation method disclosed by the invention is simple to operate, low in cost and quite suitable for industrial production.
Description
Technical field
The present invention relates to technical field of medicine, be specifically related to a kind of Linezolid (linezolid) sheet and preparation method thereof.
Background technology
Linezolid, the (oxazolidinon-5-yl-methyl)-2-thiophene-carboxamides antibiotic of synthetic, within 2000, obtain U.S. FDA approval, be used for the treatment of Grain-positive (G+) coccigenic infection, comprise by cause doubtful of MRSA or make a definite diagnosis nosocomial pneumonia (HAP), community acquired pneumonia (CAP), complexity skin or skin soft-tissue infection (SSTI) and vancomycin-resistant enterococcus (VRE) infects.
Linezolid is bacterioprotein synthetic inhibitor, acts on antibacterial 50S ribosomal subunit, and closest to site of action.Different from other medicines, Linezolid does not affect peptidyl transferase activity, just acts on the initial period of translation system, suppresses mRNA to be connected with ribosome, stops the formation of 70S initiation complex, thus inhibit the synthesis of bacterioprotein.The site of action of Linezolid and mode are unique, therefore in the positive bacteria with internal or acquired drug-resistance feature, and the antimicrobial drug generation crossing drug resistant all not easily synthesized with other Profilin, the in vitro generation of also not easily Induction of bacterial drug resistance.Research shows, usually causes positive bacteria to produce the gene pairs Linezolid of drug resistance all without impact to the antibacterials acting on 50S ribosomal subunit, comprises and there is modification enzyme, active efflux mechanisms and the modification of antibacterial target position and protective effect.
Linezolid all shows good antibacterial action to methicillin-sensitivity or resistant Staphylococcus species, vancomycin sensitive or drug resistance enterococcus, penicillin-susceptible or Antimicrobial Streptococcus Pneumoniae, also has an antibacterial activity to anaerobe.About the analysis of Linezolid sensitivity shows, Linezolid is to the methicillin-sensitivity in the 3382 strain antibacterials be separated to from skin, blood and lung or drug-resistant S. aureus, staphylococcus epidermidis, streptococcus pyogenes (Streptococcuspyogenes, a kind of A group is grown sturdily Hemolytic streptococcus), streptococcus pneumoniae, streptococcus agalactiae and Enterococcus etc. all have excellent activity, MIC50 scope is 0.5-4 mg/litre; Have moderate activity to its Moraxella of card and hemophilus influenza, MIC50 is 4-16 mg/litre.
Linezolid is a kind of multi-crystalline compounds, comprises crystalline form I, crystal form II, crystalline form III and crystalline form IV.Use II crystal formation in imported product, stable crystal form, but have patent protection.Domestic manufacturer, in order to avoid patent, all use IV crystal formation without patent protection, but the dissolubility of IV crystal formation in water is less, in water, be only slightly soluble, runs into organic solvent simultaneously and easily turns brilliant one-tenth II crystal formation.
The problem easily run in preparation is containing the Linezolid sheet process of crystalline form IV has:
1, linezolid form IV easily changes linezolid form II into, this especially more easily occurs when touching ethanol, isopropyl alcohol or water equal solvent and changes, and therefore causes tablet unstable thus produces impurity.The different crystal forms form of medicine also can affect the bioavailability, safety etc. of medicine.
2, linezolid form IV dissolubility reduces greatly, only has about 20% of II crystal formation material dissolution degree, and obtained Dissolution of Tablet only has the 20-30% of import sheet.
3, character is cotton shape, mobility extreme difference, and supplementary material is difficult to mixing.
4, specification large (600mg), dissolution is poor, if adopt hydrophilic adjuvant Macrodilution, then total tablet heavily can be very large, and take inconvenience, patient compliance is poor.
Due to the existence of above problem, obtain the Linezolid sheet relative difficult that the fast and tablet friability of stable crystal form, stripping meets pharmacopoeial requirements.
After patent CN200680026281.1 adopts direct powder compression or raw material to add polyvidone with isopropyl alcohol wet granulation again the method such as tabletting prepare Linezolid sheet.But though direct powder compression can prevent Linezolid from touching crystal conversion after solvent, in production process, dust easily flies upward, and causes the problem such as wastage of material, environmental pollution; More seriously material poor compressibility, causes the problem such as sliver, fragment serious, is difficult to the tablet obtaining meeting pharmacopoeial requirements.Simultaneously, raw material adds the method with isopropyl alcohol wet granulation tabletting again after polyvidone, preparation process is complicated, simultaneously, in production process, material inevitably contacts with isopropyl alcohol, causing linezolid form IV to change crystal form II into some extent, still there is the problem of linezolid form instability in the tablet obtained.
Patent CN 201110207573.8 have employed and uses the method that low melt wax material dissolves afterwards and Linezolid mixes.But in general use the method, melting supplementary product consumption is that about 2 times of principal agent are comparatively suitable, therefore, the less prescription of principal agent consumption is relatively applicable to.And the specification of Linezolid is very large, reaches 600mg, therefore, be not suitable for this method.
Therefore, the Linezolid sheet providing a kind of stable crystal form, dissolution high is very necessary.
Summary of the invention
The object of the invention is to overcome the technological deficiency that Linezolid in existing technical process easily changes the problem such as crystal formation, difficult miscible, poor solubility, there is provided a kind of stable, good, simple to operate, with low cost, efficient preparation technology of dissolution, with applicable industrialized great production.
For above-mentioned deficiency of the prior art, the object of the present invention is to provide a kind of IV crystal linezolid compositions that is stable, large, the external Fast Stripping of drug loading, be particularly for tablet and preparation method thereof.
Easily change linezolid form II into for linezolid form IV, the difficult problem that this changes especially more easily occurs when touching ethanol, isopropyl alcohol or water equal solvent, granulating process adopts dry granulation, avoids the contact with water, solvent.
For the difficult problem that linezolid form IV is difficult miscible in the process preparing tablet, have employed and Linezolid is pulverized, to improve its mobility and the Blending Efficiency of Blending with adjuvant, solve difficult miscible problem.
For this product specification large (600mg), require the difficult problem solving Fast Stripping with small amount adjuvant, add anhydrous citric acid and sodium bicarbonate as effervescent, thus from slice, thin piece inside " blast " its disintegrate of raising of essence ground and result of extraction.Unexpected discovery simultaneously, add in sodium bicarbonate, anhydrous citric acid are divided into part and Extra Section be significantly better than simple in add or additional merely, and in add part also extremely important with the ratio of Extra Section, add in sodium bicarbonate, anhydrous citric acid/additional be greater than 4 or be less than 0.5 time, within 15 minutes, dissolution is defective.Present invention defines in anhydrous citric acid and sodium bicarbonate and add and additional ratio, achieve beyond thought effect.
The invention provides a kind of pharmaceutical composition of Linezolid, be made up of Linezolid, sodium lauryl sulphate, copolyvidone, starch lactose, crospovidone, anhydrous citric acid, sodium bicarbonate, magnesium stearate, silicon dioxide;
In mass, wherein Linezolid is 100 parts, sodium lauryl sulphate is 1.3-8.3 part, and copolyvidone is 1.7-26.7 part, and starch lactose is 1.7-33.3 part, crospovidone is, 4.2-23.3 part, anhydrous citric acid is 1.7-26.7 part, and sodium bicarbonate is 1.7-26.7 part, magnesium stearate is 0.3-2.5 part, and silicon dioxide is 0.3-16.7 part;
Wherein adding part/Extra Section in crospovidone is 0.2-5.0;
Wherein adding part/Extra Section in anhydrous citric acid is 0.5-4.0, preferred 1.5-3.0;
Wherein adding part/Extra Section in sodium bicarbonate is 0.5-4.0, preferred 1.5-3.0;
Wherein Linezolid mean diameter≤107 μm, below d90≤243 μm, d50≤56 μm;
Wherein said compositions is tablet.
Wherein Linezolid is IV crystal formation.
Tablet containing Linezolid provided by the invention, its coatings has 2 layers, and ground floor is water barrier, and the second layer is ordinary coating layer.
Wherein Linezolid single dose is 100mg, 200mg, 300mg, 400mg or 600mg.The difference of these specifications is by formulation ingredients and amount is than constant mutually, and scaled heavily can realize.
Present invention also offers a kind of preparation method of Linezolid IV crystal formation sheet.The method comprises:
(1) Linezolid is pulverized, mean diameter≤107 μm, below d90≤243 μm, d50≤56 μm;
(2) add in Linezolid, sodium lauryl sulphate, crospovidone in part, Plasdone S-630, anhydrous citric acid and add part, add part mix homogeneously in sodium bicarbonate, put dry granulating machine and granulate;
(3) starch lactose, crospovidone Extra Section, anhydrous citric acid Extra Section, sodium bicarbonate Extra Section, magnesium stearate, silicon dioxide is added, mixing;
(4) conventional method tabletting;
(5) 2 layers of clothing are wrapped.
Wherein, coating carries out at twice, and 80% Plasdone S-630 and 20% ethyl cellulose ethanol are prepared to concentration 10% by first time, coating weight gain 0.8-1.2%; Opadry 80% alcoholic solution is prepared to concentration 8% by second time, coating weight gain 1%-2%.
Technique effect of the present invention is mainly reflected in:
1, do not use any organic solvent or water, avoid Linezolid and meet water or solvent and turn the problem that crystalline substance causes related substance to increase, product is placed 6 months experimental results and is shown, and related substance does not obviously increase;
2, anhydrous citric acid and sodium bicarbonate is added as effervescent, define in anhydrous citric acid and sodium bicarbonate and add and additional ratio, the dissolution of tablet is brought up to more than 90% in all four kinds of dissolution mediums, although the II type raw material that IV type material dissolution is obviously used not as import sheet, but after preparation, our tablet fullys meet the level of Imported Tablet, for the bioequivalence both ensureing provides guarantee, achieves beyond thought effect;
3, because moisture has larger impact to turning brilliant, and meet water in prescription containing the composition such as citric acid, sodium bicarbonate more easy to foaming, therefore, adopt the method for twice coating first increasing bag one deck water barrier, beyond thought effect is served to the stability of Linezolid sheet, through acceleration, long-term stable experiment, every testing result all conforms with the regulations;
4, simple in production process operation, with low cost, be very applicable to suitability for industrialized production.
Specific embodiment
By specific embodiment given below, clearly can understand the present invention further, but they not limitation of the invention.
Example 1-7: preparation prescription inventory
Technique:
(1) Linezolid is pulverized, mean diameter≤107 μm, below d90≤243 μm, d50≤56 μm;
(2) add in Linezolid, sodium lauryl sulphate, crospovidone in part, Plasdone S-630, anhydrous citric acid and add part, add part mix homogeneously in sodium bicarbonate, put dry granulating machine and granulate;
(3) starch lactose, crospovidone Extra Section, anhydrous citric acid Extra Section, sodium bicarbonate Extra Section, magnesium stearate, silicon dioxide is added, mixing;
(4) conventional method tabletting;
(5) wrap 2 layers of clothing, 80% Plasdone S-630 and 20% ethyl cellulose ethanol are prepared to concentration 10% by first time, coating weight gain 0.8-1.2%; Opadry (295F680001WHITE) 80% alcoholic solution is prepared to concentration 8% by second time, coating weight gain 1%-2%.
For above embodiment 1-7, do not changing each former auxiliary material, and their mutual amount is than in situation, the scaled tablet that can obtain 100mg, 200mg, 300mg, 400mg specification.Such as, its half got respectively by each material, makes 1000, can obtain 300mg/ sheet, by that analogy.
According to Chinese Pharmacopoeia version in 2010 two annex V D high effective liquid chromatography for measuring embodiment 1-7 content, related substance and dissolutions.Wherein dissolution is detect 15 minutes dissolutions in 0.1NHCl, pH4.5 acetate buffer, purified water, phosphate buffer.
Can see from above-mentioned testing result, in mass, wherein Linezolid is 100 parts, and sodium lauryl sulphate is 1.3-8.3 part, copolyvidone is 1.7-26.7 part, starch lactose is 1.7-33.3 part, and crospovidone is, 4.2-23.3 part, anhydrous citric acid is 1.7-26.7 part, sodium bicarbonate is 1.7-26.7 part, and magnesium stearate is 0.3-2.5 part, and silicon dioxide is the prescription related substance of 0.3-16.7 part, content, 15 minutes dissolutions all conform with the regulations.
Embodiment 8-12: anhydrous citric acid, sodium bicarbonate add the contrast test of total amount and feed postition
| Embodiment 8 | Embodiment 9 | Embodiment 10 | Embodiment 11 | Embodiment 12 | |
| Linezolid | 600 | 600 | 600 | 600 | 600 |
| Sodium lauryl sulphate | 10 | 10 | 10 | 10 | 10 |
| Copolyvidone | 40 | 40 | 40 | 40 | 40 |
| Starch lactose | 80 | 80 | 80 | 80 | 80 |
| Add in crospovidone | 40 | 40 | 40 | 40 | 40 |
| Crospovidone is additional | 10 | 10 | 10 | 10 | 10 |
| Add in anhydrous citric acid | 30 | 0 | 7 | 5 | 4 |
| Anhydrous citric acid is additional | 0 | 30 | 3.5 | 2.5 | 2 |
| Add in sodium bicarbonate | 30 | 0 | 7 | 5 | 4 |
| Sodium bicarbonate is additional | 0 | 30 | 3.5 | 2.5 | 2 |
| Magnesium stearate | 5 | 5 | 5 | 5 | 5 |
| Silicon dioxide | 25 | 25 | 25 | 25 | 25 |
| Make | 1000 | 1000 | 1000 | 1000 | 1000 |
Technique: with embodiment 1.
In 0.1NHCl, pH4.5 acetate buffer, purified water, phosphate buffer, 15 minutes dissolutions (%) of embodiment 8-12 are detected according to Chinese Pharmacopoeia version in 2010 two annex V D high performance liquid chromatography.
Result illustrates, anhydrous citric acid and sodium bicarbonate are divided into Nei Jia with additional, effect than add in independent or independent additional effect much better, when in mass, Linezolid is 100 parts, and when anhydrous citric acid is less than 1.7, sodium bicarbonate is less than 1.7, within 15 minutes, dissolution is by defective.
Embodiment 13-18 the: add/determination of additional ratio in sodium bicarbonate, anhydrous citric acid
Prescription:
Technique: with embodiment 1.
In 0.1NHCl, pH4.5 acetate buffer, purified water, phosphate buffer, 15 minutes dissolutions (%) of prescription 13-18 are detected according to Chinese Pharmacopoeia version in 2010 two annex V D high performance liquid chromatography.
Result illustrate, add in sodium bicarbonate, anhydrous citric acid/additional be greater than 4 or be less than 0.5 time, within 15 minutes, dissolution is defective.
Embodiment 19:
Embodiment 2 product 6 months storage conditions: temperature 25 DEG C, humidity 60%.
Under phosphate buffer four kinds of media of the acetate buffer of 0.1N HCl, pH4.5, purified water and pH 6.8, according to the dissolution determination method in this product quality standard, to embodiment 1 sample and import sheet (Si Wo, 0.6g specification, lot number: c110252, date of manufacture: in August, 2010, valid until in July, 2013) carry out detailed dissolution and compare; According to Chinese Pharmacopoeia version in 2010 two annex V D high effective liquid chromatography for measuring dissolutions.
Embodiment 2 sample and import sheet 15 minutes stripping comparing results:
Can see from experimental result above: placing 6 months constant product quality, related substances does not obviously increase.
Claims (7)
1. the compositions containing Linezolid, is made up of Linezolid, sodium lauryl sulphate, copolyvidone, starch lactose, crospovidone, anhydrous citric acid, sodium bicarbonate, magnesium stearate, silicon dioxide;
In mass, wherein Linezolid is 100 parts, sodium lauryl sulphate is 1.3-8.3 part, and copolyvidone is 1.7-26.7 part, and starch lactose is 1.7-33.3 part, crospovidone is, 4.2-23.3 part, anhydrous citric acid is 1.7-26.7 part, and sodium bicarbonate is 1.7-26.7 part, magnesium stearate is 0.3-2.5 part, and silicon dioxide is 0.3-16.7 part;
Wherein adding part/Extra Section in crospovidone is 0.2-5.0,
Wherein adding part/Extra Section in anhydrous citric acid is 0.5-4.0,
Wherein adding part/Extra Section in sodium bicarbonate is 0.5-4.0;
Wherein said compositions is tablet.
2. compositions as claimed in claim 1, is characterized in that described Linezolid is IV crystal formation.
3. compositions as claimed in claim 1, it is characterized in that adding part/Extra Section in described anhydrous citric acid is 1.5-3.0, adding part/Extra Section in sodium bicarbonate is 1.5-3.0.
4. compositions as claimed in claim 1, it is characterized in that bag 2 layers of clothing, ground floor is water barrier, and the second layer is ordinary coating layer.
5. compositions as claimed in claim 1, is characterized in that described Linezolid single dose is 100mg, 200mg, 300mg, 400mg or 600mg.
6. prepare a method for compositions described in claim 1, it is characterized in that,
(1) Linezolid is pulverized, mean diameter≤107 μm, below d90≤243 μm, d50≤56 μm;
(2) add in Linezolid, sodium lauryl sulphate, crospovidone in part, Plasdone S-630, anhydrous citric acid and add part, add part mix homogeneously in sodium bicarbonate, put dry granulating machine and granulate;
(3) starch lactose, crospovidone Extra Section, anhydrous citric acid Extra Section, sodium bicarbonate Extra Section, magnesium stearate, silicon dioxide is added, mixing;
(4) conventional method tabletting;
(5) 2 layers of clothing are wrapped.
7. preparation method as claimed in claim 6, is characterized in that described coating is coating twice, first time by 80% Plasdone S-630 and 20% ethyl cellulose with ethanol preparation to concentration 10%, coating weight gain 0.8-1.2%; Opadry 80% alcoholic solution is prepared to concentration 8% by second time, coating weight gain 1%-2%.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410821559.0A CN104586812A (en) | 2014-12-25 | 2014-12-25 | Composition containing linezolid as well as preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410821559.0A CN104586812A (en) | 2014-12-25 | 2014-12-25 | Composition containing linezolid as well as preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN104586812A true CN104586812A (en) | 2015-05-06 |
Family
ID=53113091
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410821559.0A Pending CN104586812A (en) | 2014-12-25 | 2014-12-25 | Composition containing linezolid as well as preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104586812A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113995726A (en) * | 2021-11-26 | 2022-02-01 | 深圳万乐药业有限公司 | Linezolid II crystal form tablet and preparation method thereof |
| CN118059106A (en) * | 2024-04-17 | 2024-05-24 | 山东新时代药业有限公司 | Linezolid antibacterial preparation and preparation method thereof |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070104785A1 (en) * | 2005-07-29 | 2007-05-10 | Navale Suryakant V | Tablets of linezolid form iii and processes for their preparation |
| CN101262853A (en) * | 2005-07-20 | 2008-09-10 | 特瓦制药工业有限公司 | Stable pharmaceutical composition comprising linezolid form IV |
| CN102885788A (en) * | 2011-07-22 | 2013-01-23 | 重庆华邦制药股份有限公司 | Linezolid tablets in stable crystal form and preparation method thereof |
| CN103099792A (en) * | 2012-12-10 | 2013-05-15 | 成都欣捷高新技术开发有限公司 | Preparation method of IV crystal linezolid tablets having high drug loading capacity and capable of quickly dissolving |
| CN104173303A (en) * | 2014-08-14 | 2014-12-03 | 杭州华东医药集团新药研究院有限公司 | Linezolid-containing composition and preparation method thereof |
-
2014
- 2014-12-25 CN CN201410821559.0A patent/CN104586812A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101262853A (en) * | 2005-07-20 | 2008-09-10 | 特瓦制药工业有限公司 | Stable pharmaceutical composition comprising linezolid form IV |
| US20070104785A1 (en) * | 2005-07-29 | 2007-05-10 | Navale Suryakant V | Tablets of linezolid form iii and processes for their preparation |
| CN102885788A (en) * | 2011-07-22 | 2013-01-23 | 重庆华邦制药股份有限公司 | Linezolid tablets in stable crystal form and preparation method thereof |
| CN103099792A (en) * | 2012-12-10 | 2013-05-15 | 成都欣捷高新技术开发有限公司 | Preparation method of IV crystal linezolid tablets having high drug loading capacity and capable of quickly dissolving |
| CN104173303A (en) * | 2014-08-14 | 2014-12-03 | 杭州华东医药集团新药研究院有限公司 | Linezolid-containing composition and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| 曹高忠等: "利奈唑胺凝胶的制备与质量控制", 《医药导报》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113995726A (en) * | 2021-11-26 | 2022-02-01 | 深圳万乐药业有限公司 | Linezolid II crystal form tablet and preparation method thereof |
| CN118059106A (en) * | 2024-04-17 | 2024-05-24 | 山东新时代药业有限公司 | Linezolid antibacterial preparation and preparation method thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| ES2560669T3 (en) | Compositions of stable thiacumycin | |
| TWI744224B (en) | Solid preparation | |
| CN107949375B (en) | Oral solid preparation containing irinotecan and preparation method thereof | |
| US12502384B2 (en) | Pharmaceutical composition containing nitroxoline prodrug, and preparation method and application therefor | |
| WO2022022369A1 (en) | Sustained-release formulation of tofacitinib or salt thereof and preparation method therefor | |
| AU2015312672B2 (en) | Tadalafil oral dispersible film and preparing method thereof | |
| EP3384921A1 (en) | New use of thiopeptin | |
| CN103099792B (en) | Preparation method of IV crystal linezolid tablets having high drug loading capacity and capable of quickly dissolving | |
| EP2799072A1 (en) | Solid pharmaceutical composition comprising an antibiotic from the quinolone family and method for the production thereof | |
| CN104055743B (en) | A kind of preparation method containing razaxaban oral formulations | |
| CN104523686A (en) | Acotiamide hydrochloride medicinal preparation and preparation method thereof | |
| CN112996527B (en) | Compounds and methods for treating fungal infections | |
| CN104586812A (en) | Composition containing linezolid as well as preparation method thereof | |
| CN102652737A (en) | Entecavir tablet and preparation method thereof | |
| CN104173303A (en) | Linezolid-containing composition and preparation method thereof | |
| CN103127108B (en) | Telmisartan amlodipine tablet, and preparation method and use thereof | |
| CN111214456A (en) | Voriconazole dry suspension and preparation method thereof | |
| CN103494786B (en) | Medicinal composition containing moxifloxacin hydrochloride | |
| CN102525982A (en) | Stable moxifloxacin hydrochloride medicinal composition | |
| CN106794148A (en) | The multi-mode delivery formulations of doxylamine and pyridoxol and/or its metabolite or salt | |
| CN102846577B (en) | Enteric tablet containing erythromycin cydocarbonate | |
| US20210052687A1 (en) | Plant extract-based biologically active supplement having antibacterial, antiviral and antifungal action | |
| CN103919780B (en) | Calming soporific preparation, its compound preparation, preparation method and pharmaceutical composition | |
| CN102309488A (en) | Itraconazole medicinal composition and preparation method thereof | |
| CN104644601A (en) | Capecitabine tablet |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20150506 |