CN104688730A - Carvedilol tablet and preparation method thereof - Google Patents
Carvedilol tablet and preparation method thereof Download PDFInfo
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- CN104688730A CN104688730A CN201410447344.7A CN201410447344A CN104688730A CN 104688730 A CN104688730 A CN 104688730A CN 201410447344 A CN201410447344 A CN 201410447344A CN 104688730 A CN104688730 A CN 104688730A
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- carvedilol
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- 229960004195 carvedilol Drugs 0.000 title claims abstract description 97
- NPAKNKYSJIDKMW-UHFFFAOYSA-N carvedilol Chemical compound COC1=CC=CC=C1OCCNCC(O)COC1=CC=CC2=NC3=CC=C[CH]C3=C12 NPAKNKYSJIDKMW-UHFFFAOYSA-N 0.000 title claims abstract description 97
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- 229920002472 Starch Polymers 0.000 claims abstract description 38
- 235000019698 starch Nutrition 0.000 claims abstract description 38
- 239000008107 starch Substances 0.000 claims abstract description 38
- 238000004090 dissolution Methods 0.000 claims abstract description 25
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims abstract description 24
- 238000000034 method Methods 0.000 claims abstract description 20
- 239000011734 sodium Substances 0.000 claims abstract description 16
- 229910052708 sodium Inorganic materials 0.000 claims abstract description 14
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims abstract description 13
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims abstract description 13
- 239000008108 microcrystalline cellulose Substances 0.000 claims abstract description 13
- 229940016286 microcrystalline cellulose Drugs 0.000 claims abstract description 13
- 235000019359 magnesium stearate Nutrition 0.000 claims abstract description 12
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 16
- 235000019333 sodium laurylsulphate Nutrition 0.000 claims description 16
- 239000004141 Sodium laurylsulphate Substances 0.000 claims description 15
- 239000002002 slurry Substances 0.000 claims description 14
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 13
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 11
- 239000008187 granular material Substances 0.000 claims description 8
- 239000011812 mixed powder Substances 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 239000012153 distilled water Substances 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 4
- 239000002994 raw material Substances 0.000 claims description 4
- 239000007779 soft material Substances 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 3
- 239000002245 particle Substances 0.000 claims description 3
- RCEAADKTGXTDOA-UHFFFAOYSA-N OS(O)(=O)=O.CCCCCCCCCCCC[Na] Chemical compound OS(O)(=O)=O.CCCCCCCCCCCC[Na] RCEAADKTGXTDOA-UHFFFAOYSA-N 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 27
- 238000012360 testing method Methods 0.000 description 18
- 239000003814 drug Substances 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- 239000013558 reference substance Substances 0.000 description 11
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000010521 absorption reaction Methods 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 238000003556 assay Methods 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 239000002876 beta blocker Substances 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 230000014759 maintenance of location Effects 0.000 description 4
- 239000004094 surface-active agent Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 229940097320 beta blocking agent Drugs 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- 230000033228 biological regulation Effects 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 3
- 235000019796 monopotassium phosphate Nutrition 0.000 description 3
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 3
- UCTWMZQNUQWSLP-VIFPVBQESA-N (R)-adrenaline Chemical compound CNC[C@H](O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-VIFPVBQESA-N 0.000 description 2
- 229930182837 (R)-adrenaline Natural products 0.000 description 2
- 102000003712 Complement factor B Human genes 0.000 description 2
- 108090000056 Complement factor B Proteins 0.000 description 2
- 208000032843 Hemorrhage Diseases 0.000 description 2
- 206010020772 Hypertension Diseases 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
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- 229960005139 epinephrine Drugs 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000004811 liquid chromatography Methods 0.000 description 2
- 210000003240 portal vein Anatomy 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- AQHHHDLHHXJYJD-UHFFFAOYSA-N propranolol Chemical compound C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 description 2
- 230000035485 pulse pressure Effects 0.000 description 2
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- 239000007787 solid Substances 0.000 description 2
- 239000011550 stock solution Substances 0.000 description 2
- DZUXGQBLFALXCR-UHFFFAOYSA-N (+)-(9alpha,11alpha,13E,15S)-9,11,15-trihydroxyprost-13-en-1-oic acid Natural products CCCCCC(O)C=CC1C(O)CC(O)C1CCCCCCC(O)=O DZUXGQBLFALXCR-UHFFFAOYSA-N 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 206010007558 Cardiac failure chronic Diseases 0.000 description 1
- 208000012671 Gastrointestinal haemorrhages Diseases 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 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 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- 102000004257 Potassium Channel Human genes 0.000 description 1
- 229920003081 Povidone K 30 Polymers 0.000 description 1
- 238000000862 absorption spectrum Methods 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 238000000540 analysis of variance Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000003064 anti-oxidating effect Effects 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 230000001640 apoptogenic effect Effects 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
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- IZEKFCXSFNUWAM-UHFFFAOYSA-N dipyridamole Chemical compound C=12N=C(N(CCO)CCO)N=C(N3CCCCC3)C2=NC(N(CCO)CCO)=NC=1N1CCCCC1 IZEKFCXSFNUWAM-UHFFFAOYSA-N 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
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- 210000003734 kidney Anatomy 0.000 description 1
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- 210000004185 liver Anatomy 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 108020001213 potassium channel Proteins 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 229960003712 propranolol Drugs 0.000 description 1
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Abstract
The invention discloses a carvedilol tablet and a preparation method thereof and belongs to the technical field of medicinal preparations. 1,000 carvedilol tablets contain the following components by weight: 6.25g of carvedilol, 200g of microcrystalline cellulose, 16.5g of sodium carboxymethyl starch, 2.0g of lauryl sodium sulfate, 24.0g of starch and 1.25g of magnesium stearate, wherein the carvedilol contained in the carvedilol tablets is 90%-110% of the labelled amount. The carvedilol tablet prepared by the method disclosed by the invention has the advantages of high dissolution rate, good content uniformity and stable quality.
Description
Technical field
The invention belongs to pharmaceutical preparations technology field, be specifically related to Carvedilol Tablets and preparation method thereof.
Background technology
Carvedilol be the 3rd generation beta-blocker, researched and developed by Roche Holding Ag and in 1991 listing, nineteen ninety-five FDA ratifies this medicine and is used for the treatment of chronic heart failure, and beginning in 1996 widely uses in countries in the world.It is except having retardance epinephrine β
1and β
2outside the effect of receptor, also has retardance epinephrine α
1receptor and retardance calcium, sodium, potassium channel, suppress smooth muscle cell proliferation, antiinflammatory, antioxidation, suppress prostaglandin F
1acontracting blood vessel function.Research wherein for Cardiovascular is the most deep, and effect and antioxidative effect etc. in addition for kidney, liver also receive publicity.Clinical research proves, carvedilol significantly can reduce the M & M of heart failure, and can also prevent apoptotic generation, be that conventional beta receptor blocking agent can not be compared simultaneously.Therefore, carvedilol for idiopathic light, moderate hypertension and anginal treatment, is also the unique indication of current China approval for clinical treatment at first.Its antihypertensive effect is good, and side effect is less, and having possessed the feature of safety, gentle blood pressure lowering, is the choice drug that hypertension complicated has angina pectoris or Patients With Myocardial Infarction.
As a kind of non-selective beta-blocker newly, the application of carvedilol in liver cirrhosis patient have also been obtained to be paid close attention to widely.Most of correlational study is all directed to its therapeutic effect aspect to portal vein high-pressure digestion gastrointestinal hemorrhage.Non-selective beta-blocker reduces portal vein pressure, prevention esophageal vein Rupture haemorrhag aspect as gains in depth of comprehension are positioned on, clinically the application of existing comparative maturity.Since carvedilol listing, the effect for its control gate pulse pressure aspect also has a large amount of relevant animal and clinical trial.Carvedilol as the medicine of an effective control gate pulse pressure, accept by everybody.When preventing risk of variceal bleeding or to the situation that propranolol reaction is not good, application can be considered.
Summary of the invention
The object of the invention is to disclose Carvedilol Tablets.
Another object of the present invention is the preparation method disclosing above-mentioned Carvedilol Tablets.
The object of the invention is to be achieved through the following technical solutions:
The preparation method of Carvedilol Tablets, comprises the steps:
(1), raw material is taken by every 1000 containing the recipe quantity of carvedilol 6.25g, microcrystalline Cellulose 200g, carboxymethyl starch sodium 16.5g, sodium lauryl sulphate 2.0g, starch 24.0g and magnesium stearate 1.25g;
(2), by the carvedilol of recipe quantity and carboxymethyl starch sodium, microcrystalline Cellulose adopt equal increments method to mix, cross 80 mesh sieves, make mixed powder;
(3), the starch of getting recipe quantity is dissolved in 300ml distilled water, makes the starch slurry of 8%; The sodium lauryl sulphate of recipe quantity is dissolved in starch slurry; Then by adding containing the starch slurry of sodium lauryl sulphate in mixed powder that step (2) makes, making soft material, being granulated by 18 mesh sieves;
(4), by after above-mentioned particle drying, with 16 mesh sieve granulate, add recipe quantity magnesium stearate, stir, tabletting, obtain Carvedilol Tablets, wherein containing carvedilol in Carvedilol Tablets is 90% ~ 110% of labelled amount.
Carvedilol Tablets, wherein, the composition contained in described 1000 Carvedilol Tablets is carvedilol 6.25g, microcrystalline Cellulose 200g, carboxymethyl starch sodium 16.5g, sodium lauryl sulphate 2.0g, starch 24.0g and magnesium stearate 1.25g; Wherein containing carvedilol in Carvedilol Tablets is 90% ~ 110% of labelled amount.Described Carvedilol Tablets be by described in technique scheme preparation method obtain.
Carvedilol Tablets described in technique scheme, wherein, the dissolution of described Carvedilol Tablets is more than 80% of labelled amount.
Carvedilol Tablets described in technique scheme, wherein, the stripping percentage rate > 90% of described Carvedilol Tablets in 30min.
The present invention has following beneficial effect:
1, Carvedilol Tablets of the present invention has traditional Carvedilol Tablets different on prescription, not containing fluidizer in Carvedilol Tablets of the present invention, and adopts starch slurry as adhesive in the present invention.
2, Carvedilol Tablets of the present invention is different on raw material addition sequence from traditional preparation method in preparation method, and particularly traditional handicraft is direct dry powder sheeting, and the present invention has granulation granulate process.
3, carboxymethyl starch sodium (CMS-NA) has stronger water absorption and dilatancy, comparatively fast can steep in cold water and rise, and grain expansion and not dissolving after water suction, do not form colloid solution, do not hinder the continuation of moisture to infiltrate and affect the further disintegrate of tablet, therefore can be used as superdisintegrantes, the excipient of insoluble drugs and soluble agents tablet medicine tablet.Thus, carvedilol can reach good result of extraction without the need to micronization processes.
Accompanying drawing illustrates:
1, Fig. 1 is the collection of illustrative plates that the ultraviolet visible spectrophotometry of embodiment 1 the 1st batch of product obtains;
2, Fig. 2 is the collection of illustrative plates that the ultraviolet visible spectrophotometry of embodiment 1 the 2nd batch of product obtains;
3, Fig. 3 is the collection of illustrative plates that the ultraviolet visible spectrophotometry of embodiment 1 the 3rd batch of product obtains;
4, Fig. 4 is the spectrogram of the discriminating HPLC of embodiment 1 the 1st batch of product;
5, Fig. 5 is the spectrogram of the discriminating HPLC of embodiment 1 the 2nd batch of product;
6, Fig. 6 is the spectrogram of the discriminating HPLC of embodiment 1 the 3rd batch of product;
7, Fig. 7 is Carvedilol Tablets stripping curve.
Detailed description of the invention:
Being convenient to for making technical scheme of the present invention understand, below in conjunction with concrete test example, preparation method of the present invention and the Carvedilol Tablets of preparing gained being further described.
embodiment 1:the preparation of Carvedilol Tablets:
(1), raw material is taken by every 1000 containing the recipe quantity of carvedilol 6.25g, microcrystalline Cellulose 200g, carboxymethyl starch sodium 16.5g, sodium lauryl sulphate 2.0g, starch 24.0g and magnesium stearate 1.25g;
(2), by the carvedilol of recipe quantity and carboxymethyl starch sodium, microcrystalline Cellulose adopt equal increments method to mix, cross 80 mesh sieves, make mixed powder;
(3), the starch of getting recipe quantity is dissolved in 300ml distilled water, makes the starch slurry of 8%; The sodium lauryl sulphate of recipe quantity is dissolved in starch slurry; Then by adding containing the starch slurry of sodium lauryl sulphate in mixed powder that step (2) makes, making soft material, being granulated by 18 mesh sieves;
(4), by after above-mentioned particle drying, with 16 mesh sieve granulate, add recipe quantity magnesium stearate, stir, tabletting, obtain Carvedilol Tablets.
The composition contained in every 1000 Carvedilol Tablets in obtained Carvedilol Tablets is carvedilol 6.25g, microcrystalline Cellulose 200g, carboxymethyl starch sodium 16.5g, sodium lauryl sulphate 2.0g, starch 24.0g and magnesium stearate 1.25g; Wherein containing carvedilol in Carvedilol Tablets is 90% ~ 110% of labelled amount.
The dissolution of obtained Carvedilol Tablets is more than 80% of labelled amount.
The obtained stripping percentage rate > 90% of Carvedilol Tablets in 30min.
Formula of the present invention and preparation method are determined by following method:
Prescription screening is carried out based on the dissolution of Carvedilol Tablets and the middle tablet general rule of Chinese Pharmacopoeia 2010 editions two require.The prescription consumption that formula of the present invention first fixes principal agent carvedilol is 10g, the prescription consumption of magnesium stearate is 0.5% of dry granule gross weight, and to microcrystalline Cellulose, starch, the diluent such as lactose, to CMS-Na, the disintegrating agents such as L-HPC, to starch slurry, PVP K30 aqueous solution, the different amounts of the binding agents such as HMPC aqueous solution and Surfactant sodium lauryl sulphate has carried out the orthogonal (table 1 and table 2) of 3 levels, result is as shown in table 3, wherein table 1, factor A in table 2 and table 3, B, C, D represents diluent respectively, disintegrating agent, the kind of binding agent and surfactant.
Table 1 orthogonal experiment factor and horizontal division
Table 2 prescription screening orthogonal experiment
X
1, X
2, X
3be respectively the average dissolution of each factor 1,2,3 level; X is the average between average dissolution; Extreme difference is the extreme difference between average dissolution.
Table 3 orthogonal test analysis of variance table
Can learn from table 3, factor B and factor D on the dissolution impact of sample obviously, so factor B and factor D must be selected in excellent level, should select B2 and D2, and factor A and factor C is not obvious on dissolution impact, suitable level can be selected according to practical situation.Therefore, optimizing prescriptions is A1B2C1D2, and this is consistent with the result of intuitive analysis gained.
The dissolubility of carvedilol in water is very little, must add hydrophilicity condiment in its tablet, as microcrystalline Cellulose or carboxymethylstach sodium and Surfactant SDS etc.; Different types of diluent and binding agent are on the dissolution impact of carvedilol in preparation not quite, and the consumption of different types of disintegrating agent or surfactant has considerable influence to dissolution, wherein CMS-Na is conducive to the raising of dissolution most, can show that the consumption of sodium lauryl sulphate is about 0.5% ~ 1% by the result of the factor D of table 2 orthogonal experiment, exceed this amount to dissolution also without facilitation, consumption increases again makes dissolution decline on the contrary.
Therefore, final optimizing prescriptions is:
Tablet forming technique condition:
1, granulate:
First adopt equal increments method to mix the carvedilol of recipe quantity and carboxymethyl starch sodium, microcrystalline Cellulose, cross 80 mesh sieves, make mixed powder; Recipe quantity starch is dissolved in 300ml distilled water, makes the starch slurry of 8%, and sodium lauryl sulphate is dissolved in starch slurry; Then starch slurry is added in mixed powder, make soft material, granulated by 18 mesh sieves.
2, tabletting:
Above-mentioned granule is put in baking oven after drying, with 16 mesh sieve granulate, adds magnesium stearate, stir, tabletting, obtain Carvedilol Tablets.
embodiment 2:qualified products:
One, authentication method:
(1), getting three batches of embodiments 1, to prepare the Carvedilol Tablets fine powder of gained appropriate, add 0.06mol/L acetic acid solution carvedilol is dissolved and makes the solution about containing carvedilol 20 μ g in every lml, filter, get filtrate to measure according to ultraviolet visible spectrophotometry (Chinese Pharmacopoeia 2010 editions two annex IV A), there is absorption maximum at the wavelength place of 285nm, 319nm, 331nm, should be 0.40 ~ 0.44 in the absorbance ratio at 331nm and 285nm wavelength place.
(2), in the chromatogram recorded under " test example 1: assay " item, the retention time of need testing solution main peak should be consistent with the retention time of reference substance solution main peak.Carvedilol reference substance (Ningbo Tian Heng pharmaceutical Co. Ltd, purity: 100.0%, lot number: 130701).
Two, result:
(1), result as shown in Figures 1 to 3, three batch sample laboratory observations, have absorption maximum at the wavelength place of 285nm, 319nm, 331nm, and the absorbance ratio at 331nm and 285nm wavelength place is between 0.40 ~ 0.44.
(2) identify collection of illustrative plates as shown in figures 4-6, in the chromatogram of three batch sample records under assay item, the retention time of test sample main peak is consistent with the retention time of reference substance.
Below by way of concrete test example, the beneficial effect that preparation method of the present invention and the Carvedilol Tablets preparing gained have is described:
test example 1: assay:
Assay method: high effective liquid chromatography for measuring.
One, instrument and reagent:
(Agilent 1100, is contained in G1322A line degasser to Agilent company of U.S. high performance liquid chromatograph; G1310 quaternary pump; G1313A automatic sampler; G1316A column oven, G1315A DAD detector; HP Chemstation chemistry is stood); Acetonitrile is chromatographically pure; Carvedilol reference substance (purity: 100.0%, lot number: 130701, Ningbo Tian Heng pharmaceutical Co. Ltd); Potassium dihydrogen phosphate (Beijing Chemical Plant, analytical pure); Phosphoric acid (Red Star chemical plant, Beijing, analytical pure); Sodium hydroxide (Beijing Chemical Plant, analytical pure); Hydrochloric acid (Red Star chemical plant, Beijing, analytical pure).
Two, the selection of chromatographic condition:
Be filler with octadecylsilane chemically bonded silica; With 0.02mol/L potassium dihydrogen phosphate (by phosphoric acid adjust ph to 3.5)-acetonitrile (65:35) for mobile phase; Determined wavelength is 241nm.Get carvedilol reference substance and be about 12.5mg, put in conical flask, add 5mol/L hydrochloric acid solution 5ml, heat 3 hours in 95 DEG C of water-baths, let cool, add 5mol/L sodium hydroxide solution 5ml, mobile phase 15ml, supersound process 10 minutes, shake hook, filter, get subsequent filtrate 10 μ l, note people chromatograph of liquid, number of theoretical plate calculates by carvedilol peak and is not less than 2000, and carvedilol main peak should be greater than 6.5 with the separating degree at most degradation thing peak thereafter.
Card dimension ground falls to being greater than 6.5 with the separating degree at related substance peak, by suitably regulating the ratio of acetonitrile and potassium dihydrogen phosphate (pH3.5) to reach requirement.
Three, the preparation of solution:
1, the preparation of reference substance solution: get carvedilol reference substance, accurately weighed, dissolve with mobile phase and quantitatively dilute and make the solution of every lml containing 0.lmg, shake up, filter, get subsequent filtrate as need testing solution.
2, the preparation of need testing solution: Example 1 prepares the Carvedilol Tablets 20 of gained, accurately weighed, porphyrize, precision takes in right amount (being about equivalent to carvedilol 10mg), puts in 100ml measuring bottle, add mobile phase appropriate, supersound process makes carvedilol dissolve, and is diluted to scale with mobile phase, shakes up, filter, get subsequent filtrate as need testing solution.
Four, sample determination result:
As stated above, accurate absorption reference substance solution and need testing solution 10 μ l respectively, injection liquid chromatography, utilizes the content of carvedilol in one point external standard method calculation sample, the results are shown in Table 4.
The assay result of table 4 three batch sample carvedilol
Result shows, three batch sample carvedilol content, between 90% ~ 110% of labelled amount, meet States Pharmacopoeia specifications.
test example 2:determination of Content Uniformity:
Example 1 prepares each 10 of three batch samples of gained, put in 50ml measuring bottle (6.25mg specification) respectively, add mobile phase appropriate, supersound process makes carvedilol dissolve and is diluted to scale, shake up, filter, get subsequent filtrate as need testing solution, use high-performance liquid chromatography method content according to " two, the selection of chromatographic condition: " in test example 1; Limit is 15% (" Chinese Pharmacopoeia " version in 2010 two annex X E).The results are shown in Table 5.
Table 5 Determination of karvedilol tablets cloud test result
Result: in three batches, the A+1.80S of test agent is respectively 7.56,6.26,5.42, is all less than 15.0, meets States Pharmacopoeia specifications.
test example 3:dissolution determination:
Medicine infiltration rate in vivo is usually determined by the speed dissolved, dissolution means that medicine is from the solid preparations such as the tablet speed of stripping and degree the solvent of regulation, be medicine play curative effect important step, can its size directly affect medicine and enter blood and the key factor reaching blood drug level safely and effectively within a certain period of time, dissolution rate height illustrates that the complete degree of stripping of medicine is high, and the degree be absorbed and utilized by the body is just high.
Dissolution due to solid drugs is the key factor affecting bioavailability and clinical efficacy in medicine body, and carvedilol is water-insoluble medicine, dissolution is related to the absorption of medicine, therefore dissolution is as one of the important indicator of quality control, to ensureing that the curative effect of clinical application is significant.The present invention prepares the Carvedilol Tablets of gained to embodiment 1 dissolution according to the method for dissolution determination in pharmacopeia measures, and concrete grammar is as follows:
(1), measure the selection of wavelength and get right amount of auxiliary materials in carvedilol reference substance, Carvedilol Tablets and prescription, use (9 → 1000) hydrochloric acid solution to prepare into about 8 μ gml respectively
-1solution, by spectrophotometry, scan between wavelength 200 ~ 400nm, record absorption spectrum, at 241nm wavelength, there is absorption maximum at place, and adjuvant is noiseless, therefore adopt 241nm as mensuration wavelength.
(2), linear test gets carvedilol reference substance 0.5mg, is mixed with 100 μ gml with (9 → 1000) hydrochloric acid solution
-1the stock solution of concentration, draws stock solution respectively and is mixed with 5,10,15,20,5 and 30 μ gml
-1carvedilol measure solution, contrast spectrophotography, 241nm wavelength place measure trap.With trap to concentration linear regression, obtain regression equation A=0.0991C+0.0784 (R
2=0.9991), show at 5 ~ 30 μ gml
-1scope has good linear relationship.
(3), dissolution determination method Example 1 prepares three batch samples of gained, according to dissolution method (Chinese Pharmacopoeia 2010 editions two, annex X C first method), with hydrochloric acid solution (9 → 1000) 900ml for dissolution medium, rotating speed is 100 turns per minute, operate in accordance with the law, respectively 5,10,20,30,50min samples 9ml (supplying hydrochloric acid solution after every sub-sampling), filter; Separately getting carvedilol reference substance uses (9 → 1000) hydrochloric acid solution to be mixed with 6.25 μ gml in right amount
-1solution;
Get above-mentioned two kinds of solution, measure trap according to ultraviolet visible spectrophotometry (Chinese Pharmacopoeia 2010 editions two annex IV A) at 241nm place, calculate the dissolution of every sheet, and make accumulative stripping percentage curves figure, limit is 80% of labelled amount, should conform with the regulations.As shown in Figure 7, Fig. 7 is three batch sample Carvedilol Tablets stripping curves to result, and wherein " ▲ " symbol represents the 1st batch sample, and " ◆ " symbol represents the 2nd batch sample, and " ■ " symbol represents the 3rd batch sample.
Result: three batch sample carvedilol stripping percentage rate > 90% in 30min, all conform with the regulations.
The above, be only preferred embodiment of the present invention, not any formal and substantial restriction is done to the present invention, all those skilled in the art, do not departing within the scope of technical solution of the present invention, when utilizing disclosed above technology contents, and a little change made, modify with differentiation equivalent variations, be Equivalent embodiments of the present invention; Meanwhile, all according to substantial technological of the present invention to the change of any equivalent variations that above embodiment is done, modify and differentiation, all still belong in the scope of technical scheme of the present invention.
Claims (4)
1. the preparation method of Carvedilol Tablets, comprises the steps:
(1), raw material is taken by every 1000 containing the recipe quantity of carvedilol 6.25g, microcrystalline Cellulose 200g, carboxymethyl starch sodium 16.5g, sodium lauryl sulphate 2.0g, starch 24.0g and magnesium stearate 1.25g;
(2), by the carvedilol of recipe quantity and carboxymethyl starch sodium, microcrystalline Cellulose adopt equal increments method to mix, cross 80 mesh sieves, make mixed powder;
(3), the starch of getting recipe quantity is dissolved in 300ml distilled water, makes the starch slurry of 8%; The sodium lauryl sulphate of recipe quantity is dissolved in starch slurry; Then by adding containing the starch slurry of sodium lauryl sulphate in mixed powder that step (2) makes, making soft material, being granulated by 18 mesh sieves;
(4), by after above-mentioned particle drying, with 16 mesh sieve granulate, add recipe quantity magnesium stearate, stir, tabletting, obtain Carvedilol Tablets, wherein containing carvedilol in Carvedilol Tablets is 90% ~ 110% of labelled amount.
2. Carvedilol Tablets, is characterized in that: the composition contained in described 1000 Carvedilol Tablets is carvedilol 6.25g, microcrystalline Cellulose 200g, carboxymethyl starch sodium 16.5g, sodium lauryl sulphate 2.0g, starch 24.0g and magnesium stearate 1.25g; Wherein containing carvedilol in Carvedilol Tablets is 90% ~ 110% of labelled amount.
3. Carvedilol Tablets according to claim 2, is characterized in that: the dissolution of described Carvedilol Tablets is more than 80% of labelled amount.
4. Carvedilol Tablets according to claim 2, is characterized in that: the stripping percentage rate > 90% of described Carvedilol Tablets in 30min.
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Application publication date: 20150610 |