CN103006598B - The blood pressure lowering tablet of sodium chloride-containing pharmaceutical carrier - Google Patents
The blood pressure lowering tablet of sodium chloride-containing pharmaceutical carrier Download PDFInfo
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- CN103006598B CN103006598B CN201210587700.6A CN201210587700A CN103006598B CN 103006598 B CN103006598 B CN 103006598B CN 201210587700 A CN201210587700 A CN 201210587700A CN 103006598 B CN103006598 B CN 103006598B
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- candesartan cilexetil
- sodium chloride
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Abstract
The present invention relates to the blood pressure lowering tablet of sodium chloride-containing pharmaceutical carrier, it is applicable to pharmacy corporation.It discloses containing sodium chloride, candesartan Cilexetil and pharmaceutically acceptable adjuvant.Sodium chloride stable in properties, water solublity and compressibility good, and with candesartan Cilexetil, there is the good compatibility, using sodium chloride as the carrier of candesartan Cilexetil, by spraying into polyethylene glycol 6000 or PEG 8000 liquid, by medicine appendix at sodium chloride and containing on the mixed carrier of other pharmaceutically acceptable adjuvant, then tabletting after the adjuvant mix homogeneously such as lubricant is added, can be compressing at low pressures, reduce pressure during tabletting, can avoid in tableting processes, making because pressure is high candesartan Cilexetil be transformed into unstable crystal form thus content in storage process is declined, impurity increases.The candesartan cilexetil good stability that the present invention obtains, release are rapidly.
Description
Technical field
The present invention is specifically related to the blood pressure lowering tablet of sodium chloride-containing pharmaceutical carrier, belongs to medical art.
Background technology
" Chinese residents nutrition and the Health Situation " of Ministry of Public Health announcement in 2004 shows China 18 years old and above prevalence of hypertension rate is 18.8%, estimates national number of patients more than 1.6 hundred million." National archives of Environmental Health " display that World Health Organization (WHO) in 2005 announces, hypertension has become one of large chronic disease of China ten, is also one of high disease of ten large fatality rate.
Candesartan Cilexetil (being after this sometimes called " active component ") is angiotensin
aT
1receptor antagonist, is hydrolyzed to active metabolite Candesartan in vivo, by with vascular smooth muscle AT
1receptors bind and antagonizing angiotensin
vasoconstrictor effects, thus reduce peripheral vascular resistance.This medicine is through long-term clinical practice, be proved and had reliable antihypertensive effect, toxic and side effects is few simultaneously, and adverse reaction rate is lower, little on the be correlated with impact of organ of metabolism while reducing blood pressure, therefore become a kind of common drug for the long-term blood pressure lowering of hyperpietic.
As everyone knows, guarantee that drug molecule is medicine is steadily played a role effectively and one of the most basic means reducing side effect that catabolite brings from keeping stablizing in being taken by human body before, candesartan Cilexetil is no exception.The candesartan cilexetil former research and development published patent of Takede Chemical Industries Ltd of Japan of producer (patent No. ZL93100008.4) provides the compositions of a kind of candesartan Cilexetil (being expressed as the compound with general structure V in the description of this patent) and low melting point oiliness compound (mainly the Polyethylene Glycol of various molecular weights rank), said composition is through suitable technique and lactose, corn starch, hyprolose, carboxymethylcellulose calcium, after the adjuvant mixing such as magnesium stearate, owing to decreasing in kneading, granulate and the crystal confusionization that causes of molding process under high pressure, thus make candesartan Cilexetil still can keep chemically more stable crystal form after molding, thus significantly improve stability.But according to the embodiment of this patent, its formula is all using lactose as major auxiliary burden, placing condition stability inferior soprano at the residue content of placement after 4 weeks at 50 DEG C is 99.4% of content before placement, the lowest is placed and is namely low to moderate 98.9% in one week, disclose the tablet that the formula containing adjuvants such as lactose, corn starch, hyprolose, carboxymethylcellulose calcium, polyethylene glycol 6000s is prepared by method disclosed in its patent, even in the short period, its content still declines comparatively large at 50 DEG C, catabolite is more.
According to Japanese Takede Chemical Industries Ltd commercialized product must Loews sheet open source information display, containing adjuvants such as lactose, corn starch, hyprolose, carboxymethylcellulose calcium and polyethylene glycol 6000s in its formula, adjuvant used is consistent with above-mentioned patent, Japan's Takede Chemical Industries Ltd commercialized product must data consistent in the study on the stability result of Loews sheet and above-mentioned patent Example, and with the prolongation of period of storage, degradation impurity is more.
European patent EP 0546358B1 discloses moisture Gao Shihui in preparation and causes candesartan Cilexetil to be degraded, and the stability of candesartan Cilexetil can be affected during tableting pressure height, therefore should not water content be used in a large number high and stronger portion of cellulose class, starch based, the polyvinylpyrrolidone class adjuvant of water absorption, and also should not use when needing pressure higher could the adjuvant of compression molding.
Summary of the invention
Object of the present invention aims to provide the tablet of candesartan Cilexetil, and it can improve the stability of active component further on the basis of existing product and technology, has rate of release faster simultaneously.
In order to solve the problem, the tablet that technical solution of the present invention is sodium chloride-containing, candesartan Cilexetil and pharmaceutically acceptable adjuvant are made, its stability is very good, and release quickly.
Tablet of the present invention, be that the weight that every sheet contains candesartan Cilexetil is 4mg ~ 32mg, the weight ratio of sodium chloride is 40% ~ 90%.
The preferable range that every sheet of the present invention contains the weight ratio of sodium chloride is above 50% ~ 85%.
The present invention uses sodium chloride as the major auxiliary burden of this product and pharmaceutical carrier, because sodium chloride is the highly stable neutral compound of physicochemical property, chemical reaction can not occur with candesartan Cilexetil, the compatibility is very good, and sodium chloride is soluble in water, be conducive to stripping and the release of insoluble drug; Sodium chloride water content very low (States Pharmacopoeia specifications loss on drying is no more than 0.5%) in addition, and under the production environment of relative humidity below 70%, it draws moist very low, and sodium chloride is cubic crystal, have very excellent can molded property, at lower pressures can compression molding.The tablet stability adopting sodium chloride to make as candesartan Cilexetil pharmaceutical carrier is very good, and release quickly.
Tablet prepared by the present invention significantly reduces the pressure needed for tabletting, thus inhibits due to the crystal form confusion that high pressure causes in tableting processes, thus the generation of the situation causing active component stability to reduce.Tablet the present invention prepared places investigation under room temperature and 50 DEG C of conditions, and it is few that result shows tablet related substance prepared by the present invention, and stripping is rapid.
Advantage of the present invention is the characteristic that candesartan cilexetil has good stability and release fast.
Detailed description of the invention
Be below specific embodiments of the invention, but do not represent that the present invention is only limitted to following examples.
embodiment 1 the preparation of candesartan cilexetil
1. formula: in table 1
table 1 candesartan Cilexetil slice prescription (1000, unit: g)
2. preparation method:
1) take polyethylene glycol 6000 in the ratio of formula, be heated to 70 ~ 75 DEG C, be fused into liquid (
).
2) candesartan Cilexetil, sodium chloride, cross-linked carboxymethyl cellulose sodium (or carboxymethylstach sodium) mix homogeneously is taken respectively in the ratio of formula; add in turbine granulator; open turbine granulator, controls inlet temperature and makes temperature of charge remain on 25 ~ 40 DEG C, will (
) be slowly sprayed onto on material by aerodynamic atomization, sprayed rear discharging, granulate, obtain candesartan Cilexetil granule (
).
3) in the ratio of formula take magnesium stearate with (
) mix homogeneously, with 15kN/cm
2following pressure tabletting.
embodiment 2 the preparation of candesartan cilexetil
1. formula: in table 2
table 2 candesartan Cilexetil slice prescription (1000, unit: g)
2. preparation technology:
1) take PEG 8000 in the ratio of formula, be heated to 70 ~ 80 DEG C, be fused into liquid (
).
2) candesartan Cilexetil, sodium chloride, cross-linked carboxymethyl cellulose sodium (or carboxymethylstach sodium) mix homogeneously is taken respectively in the ratio of formula; add in turbine granulator; open turbine granulator, controls inlet temperature and makes temperature of charge remain on 25 ~ 40 DEG C, will (
) be slowly sprayed onto on material by aerodynamic atomization, sprayed rear discharging, granulate, obtain candesartan Cilexetil granule (
).
3) in the ratio of formula take magnesium stearate with (
) mix homogeneously, with 15kN/cm
2following pressure tabletting.
The sheet obtained by formula in embodiment 1 ~ 6 and Japanese Takede Chemical Industries Ltd commercialized product must the dissolution of Loews sheet and stability compare, result shows that tablet related substance prepared by the present invention is few, and stripping is rapid, there is the characteristic of good stability and release fast.
One, dissolution rate and dissolution rate increase the investigation of change with period of storage
According to dissolution method (Chinese Pharmacopoeia 2010 editions two annex XC), with 1% polysorbate 20 solution 900mL for dissolution medium, 37 DEG C, slurry processes, rotating speed is 50rpm, in Evaluation operation example each formula and Japanese Takede Chemical Industries Ltd commercialized product must the dissolving out capability of active component in Loews sheet, concrete evaluation methodology be 0 time taking sample determination 15,30,45min time dissolution, storage 2 years afterwards sampling be measured in the same method.The results are shown in Table 3.
table 3 dissolution determination result (%)
The candesartan Cilexetil that table 3 shows formula 1 ~ 6 all can Fast Stripping and speed significantly must Loews sheet faster than Japanese Takede Chemical Industries Ltd commercialized product, illustrate that invention formulation has good dissolved corrosion.And along with the passing of period of storage, dissolution rate, also without significant change, and must show excellent preparation performance compared with Loews sheet.
Two, the investigation of stability
This investigates determination used and determination of related substances method ratifies tentative candesartan cilexetil standard (YBH16872005) from state food and drug administration, and method is summarized as follows:
Related substance: after getting porphyrize, sample is appropriate, after mobile phase ultrasonic dissolution, filtration and dilution, measure according to high performance liquid chromatography (Chinese Pharmacopoeia version in 2010 two annex VD) by following condition: take octadecylsilane chemically bonded silica as chromatographic column filler; With acetonitrile-water-methanol (63:33:4) (with phosphoric acid adjust ph 3.0-3.5) for mobile phase; Determined wavelength is 255nm.
Determination: the condition working sample in photograph determination of related substances method and the candesartan Cilexetil peak area of standard substance, and calculate the content of sample.
1. the investigation of long-time stability
The tablet prepared in the embodiment of the present invention and Japanese Takede Chemical Industries Ltd commercialized product must be placed 2 years by Loews sheet under normal temperature condition, the changes of contents of sampling and measuring related substance and active component (with 0 time content be 100% content), the results are shown in Table 4.
the long-time stability of table 4 candesartan cilexetil investigate result
Table 4 is placed by room temperature the study on the stability result kept sample and is shown, and via the tablet that the embodiment of the present invention is obtained, its active component has good stability, and must have significant advantage compared with Loews sheet with Japanese Takede Chemical Industries Ltd commercialized product.
2.50 DEG C of accelerated stabilities are investigated
By preparation obtained for formula each in the embodiment of the present invention and Japanese Takede Chemical Industries Ltd commercialized product must Loews sheet be placed in 50 DEG C of conditions under place 12 weeks, and using 0 time testing result as 100% content, check its changes of contents situation, the value (patent No. ZL93100008.4) of the embodiment of contained to result and document optimum is compared, in table 5.
the 50 DEG C of placements of table 5 candesartan cilexetil keep sample changes of contents situation
Comprehensive above-mentioned testing result, we can from 0 time dissolution, storage after 2 years and 50 DEG C place after dissolution, content and related substance total amount 4 aspects invention formulation and Japanese Takede Chemical Industries Ltd commercialized product must be compared by Loews sheet.Following conclusion is easily drawn: 1) from measurement result. the 15min stripping quantity of invention formulation 0 time is all higher than 70%, and being significantly higher than must the level of Loews agreement that contracts a film or TV play to an actor or actress 36%, in dissolution rate, have significant advantage; 2). after invention formulation stores 2 years, dissolution rate is almost unchanged, the dissolution rate of Loews sheet must then have larger decline; 3). after invention formulation stores 2 years, be reduced to 1% under content, and about 3.5% must be have dropped by Loews sheet content; Place after 4 weeks, be reduced to 0.5% under invention formulation content, then must have dropped 0.8% by Loews sheet content for 50 DEG C; Place after 12 weeks for 50 DEG C, invention formulation content declines many lower than 0.5%, content higher than bibliographical information 4 weeks optimal values and the content value of 12 weeks must be placed by Loews sheet; 4). after invention formulation stores 2 years, related substance total amount can be controlled in the level lower than 0.7% substantially, and must reach 1.63% by Loews sheet.So can think that invention formulation must have significant preparation performance advantage compared with Loews sheet with Japanese Takede Chemical Industries Ltd commercialized product.
Claims (6)
1. the blood pressure lowering tablet of sodium chloride-containing pharmaceutical carrier, is characterized in that 1000 slice prescriptions are: candesartan Cilexetil 16g, sodium chloride 60g, cross-linked carboxymethyl cellulose sodium 6g, PEG 8000 9g, magnesium stearate 1g, 1. preparation method is: take PEG 8000 in the ratio of formula, be heated to 70 ~ 80 DEG C, be fused into liquid (I), 2.: take candesartan Cilexetil respectively in the ratio of formula, sodium chloride, cross-linked carboxymethyl cellulose sodium mix homogeneously, add in turbine granulator, open turbine granulator, controlling inlet temperature makes temperature of charge remain on 25 ~ 40 DEG C, liquid (I) is slowly sprayed onto on material by aerodynamic atomization, spray rear discharging, granulate, obtain candesartan Cilexetil granule (II), 3.: take magnesium stearate in the ratio of formula and mix homogeneously with candesartan Cilexetil granule (II), with 15kN/cm
2following pressure tabletting.
2. the blood pressure lowering tablet of sodium chloride-containing pharmaceutical carrier, is characterized in that 1000 slice prescriptions are: candesartan Cilexetil 8g, sodium chloride 120g, carboxymethylstach sodium 5g, PEG 8000 7g, magnesium stearate 1g; Preparation method is: 1. take PEG 8000 in the ratio of formula, is heated to 70 ~ 80 DEG C, is fused into liquid (I);
2. candesartan Cilexetil, sodium chloride, carboxymethylstach sodium mix homogeneously is taken respectively in the ratio of formula, add in turbine granulator, open turbine granulator, controlling inlet temperature makes temperature of charge remain on 25 ~ 40 DEG C, liquid (I) is slowly sprayed onto on material by aerodynamic atomization, spray rear discharging, granulate, obtain candesartan Cilexetil granule (II);
3. take magnesium stearate in the ratio of formula to mix homogeneously with candesartan Cilexetil granule (II), with the pressure tabletting of below 15kN/cm2.
3. the blood pressure lowering tablet of sodium chloride-containing pharmaceutical carrier, is characterized in that 1000 slice prescriptions are: candesartan Cilexetil 4g, sodium chloride 150g, carboxymethylstach sodium 5g, PEG 8000 7g, magnesium stearate 1g; Preparation method is: 1. take PEG 8000 in the ratio of formula, is heated to 70 ~ 80 DEG C, is fused into liquid (I);
2. candesartan Cilexetil, sodium chloride, carboxymethylstach sodium mix homogeneously is taken respectively in the ratio of formula, add in turbine granulator, open turbine granulator, controlling inlet temperature makes temperature of charge remain on 25 ~ 40 DEG C, liquid (I) is slowly sprayed onto on material by aerodynamic atomization, spray rear discharging, granulate, obtain candesartan Cilexetil granule (II);
3. take magnesium stearate in the ratio of formula to mix homogeneously with candesartan Cilexetil granule (II), with the pressure tabletting of below 15kN/cm2.
4. the blood pressure lowering tablet of sodium chloride-containing pharmaceutical carrier, is characterized in that 1000 slice prescriptions are: candesartan Cilexetil 32g, sodium chloride 32g, cross-linked carboxymethyl cellulose sodium 7g, polyethylene glycol 6000 8g, magnesium stearate 1g; Preparation method is: 1. take polyethylene glycol 6000 in the ratio of formula, is heated to 70 ~ 75 DEG C, is fused into liquid (I);
2. candesartan Cilexetil, sodium chloride, cross-linked carboxymethyl cellulose sodium mix homogeneously is taken respectively in the ratio of formula, add in turbine granulator, open turbine granulator, controlling inlet temperature makes temperature of charge remain on 25 ~ 40 DEG C, liquid (I) is slowly sprayed onto on material by aerodynamic atomization, spray rear discharging, granulate, obtain candesartan Cilexetil granule (II);
3. take magnesium stearate in the ratio of formula to mix homogeneously with candesartan Cilexetil granule (II), with the pressure tabletting of below 15kN/cm2.
5. the blood pressure lowering tablet of sodium chloride-containing pharmaceutical carrier, is characterized in that 1000 slice prescriptions are: candesartan Cilexetil 32g, sodium chloride 45g, cross-linked carboxymethyl cellulose sodium 6g, polyethylene glycol 6000 6g, magnesium stearate 1g; Preparation method is: 1. take polyethylene glycol 6000 in the ratio of formula, is heated to 70 ~ 75 DEG C, is fused into liquid (I);
2. candesartan Cilexetil, sodium chloride, cross-linked carboxymethyl cellulose sodium mix homogeneously is taken respectively in the ratio of formula, add in turbine granulator, open turbine granulator, controlling inlet temperature makes temperature of charge remain on 25 ~ 40 DEG C, liquid (I) is slowly sprayed onto on material by aerodynamic atomization, spray rear discharging, granulate, obtain candesartan Cilexetil granule (II);
3. take magnesium stearate in the ratio of formula to mix homogeneously with candesartan Cilexetil granule (II), with the pressure tabletting of below 15kN/cm2.
6. the blood pressure lowering tablet of sodium chloride-containing pharmaceutical carrier, is characterized in that 1000 slice prescriptions are: candesartan Cilexetil 8g, sodium chloride 70g, carboxymethylstach sodium 6g, polyethylene glycol 6000 8g, magnesium stearate 1g; Preparation method is: 1. take polyethylene glycol 6000 in the ratio of formula, is heated to 70 ~ 75 DEG C, is fused into liquid (I);
2. candesartan Cilexetil, sodium chloride, carboxymethylstach sodium mix homogeneously is taken respectively in the ratio of formula, add in turbine granulator, open turbine granulator, controlling inlet temperature makes temperature of charge remain on 25 ~ 40 DEG C, liquid (I) is slowly sprayed onto on material by aerodynamic atomization, spray rear discharging, granulate, obtain candesartan Cilexetil granule (II);
3. take magnesium stearate in the ratio of formula to mix homogeneously with candesartan Cilexetil granule (II), with the pressure tabletting of below 15kN/cm2.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006079496A1 (en) * | 2005-01-26 | 2006-08-03 | Lek Pharmaceuticals D.D. | New pharmaceutical composition containing candesartan cilexetil as lipophilic crystalline substance |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006079496A1 (en) * | 2005-01-26 | 2006-08-03 | Lek Pharmaceuticals D.D. | New pharmaceutical composition containing candesartan cilexetil as lipophilic crystalline substance |
Non-Patent Citations (1)
| Title |
|---|
| The use of sodium chloride as a directly compressible filler. III. Drug-to-filler ratio;HAMMOUDA Y etal;《Pharm Ind》;19781231;第40卷(第9期);第987-992页 * |
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