CN101176723A - Ranolazine sustained release tablets - Google Patents
Ranolazine sustained release tablets Download PDFInfo
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- CN101176723A CN101176723A CNA2007103012621A CN200710301262A CN101176723A CN 101176723 A CN101176723 A CN 101176723A CN A2007103012621 A CNA2007103012621 A CN A2007103012621A CN 200710301262 A CN200710301262 A CN 200710301262A CN 101176723 A CN101176723 A CN 101176723A
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Abstract
The invention relates to a Reynolds pyrazine slow-released tablet, which is characterized in that the tablet comprises not more than 50wt% Reynolds pyrazine and at least an independent adhesive with 1-20wt% low viscosity PH and a or a plurality of independent adhesive with 1-20wt% high viscosity PH.
Description
Technical field:
The present invention relates to the slow releasing tablet of a kind of novel formulation of medicine ranolazine, particularly ranolazine.
Background technology:
Ranolazine, its chemistry is by name: N-(2, the 6-3,5-dimethylphenyl)-4-[2-hydroxyl-3-(2-methoxy phenoxy) propyl group]-1-piperazine acetamide
Its structural formula is:
Divide in formula: C
24H
33N
3O
4
Molecular weight: 427.54
Pharmacology type: partial fatty acid oxidation enzyme inhibitor
Mechanism of action: ranolazine is a kind of local fat oxidase inhibitor, can reduce the heart oxygen demand by enzyme regulation, improves the imbalance between the oxygen supply and demand, alleviates the symptom of regional myocardial ischemia.In addition, ranolazine also can be strengthened the glucose oxidase effect, thereby be increased the heart coefficient of oxygen utilization by regulating the metabolism of body when reducing the free fatty Oxidation.
Indication: chronic stable angina pectoris.
Angina pectoris is a cardiovascular disease more common in the coronary heart disease, and along with the raising of people's living standard and the variation of life style, its sickness rate is continuous ascendant trend.In the U.S., have at least 7,000,000 people to suffer from chronic angina pectoris, these patients' work and limitation of activity are 2-3 times of general population.Although major progress constantly appears in the coronary artery myocardial revascularization, Most patients still need be taken antianginal drug and be prevented angina pectoris attacks.Even but give coronary artery myocardial revascularization and Drug therapy, still have 26% patient angina pectoris attacks to occur.
The basic role pattern of generally acknowledging anti-anginal drug is: improve the equilibrium of supply and demand of myocardium oxygen, promptly increase coronary flow or reduce myocardial performance or both have concurrently.The medicine that is widely used in ischemic heart desease comprises nitrate esters, β
2Adrenergic receptor blocker, calcium-channel antagonists etc., these medicines all are by decreased heart rate (HR), bring high blood pressure down or weaken cardiac pumping function, thereby the heart acting is reduced with the allevating angina pectoris symptom, but they also produce further infringement to weak cardiac function simultaneously.
Sublingual administration nitroglycerin when at present, anginal common treatment is for outbreak.Antianginal drug is taken in recurrence often, as beta-Blocking agent, calcium channel blocker and long-acting nitrate.These medicines all are by decreased heart rate, bring high blood pressure down or weaken cardiac pumping function, thereby reduce the heart acting.But most of patient with angina pectoris produce further infringement to this weak cardiac function again all with congested cardiac insufficiency, chronic lung disease or diabetes.Some medicine also increases cardiac flow by coronary artery dilator.Use the above-mentioned three class anti-anginal drugs can only the allevating angina pectoris symptom.In fact, the patient with angina pectoris more than 65% is all taken two or more Drug therapy.Untoward reaction such as that the patient that great majority are taken said medicine can occur is tired, headache, extremity are ice-cold, edema and sexual impotence.Though these untoward reaction do not threaten patient's life, they have a strong impact on the quality of life of patient with angina pectoris.Directly increasing heart blood supply is anginal another means of treatment.The patient can open the coronary artery that has blocked by balloon angioplasty and coronary bypass-forming operation, thereby improves heart blood supply.But, if relatively disperseing, the coronary artery disease position should not perform the operation, operative treatment is than Drug therapy expense costliness in addition, and still need take maintenance drug therapy after operation.Therefore, be badly in need of a kind of anti-anginal drug of efficient, low toxicity at present.Ranolazine is one of newtype drug that is used in the first batch chronic stable angina pectoris.
Ranolazine is developed by U.S. CV company, belongs to the partial fatty acid oxidation enzyme inhibitor, is a kind of new drug in the metabolism therapy of resisting myocardial ischemia, and also is unique so far antianginal drug that does not cause heart rate and blood pressure change.Ranolazine reduces myocardium requirementing keto quantity by changing the energy metabolism of myocardial mode, its mechanism of action is different from traditional anti-anginal drug, characteristics are to reduce fatty acid oxidation, increase glucose oxidase, utilize glucose oxidase per unit oxygen higher and heart is done more many merit, bring into play ischemia resisting and antianginal effect than the fatty acid oxidation production capacity, simultaneously hemodynamics there is not influence, use the back that heart rate and blood pressure are not had influence, can improve the quality of life of patient with angina pectoris, the very big market competitiveness is arranged.
The ranolazine of U.S. CV Therapeutics company exploitation has obtained the permission of U.S. food Drug Administration on January 31st, 2006, is used for the chronic anginal treatment of specific crowd, thereby makes the angina pectoris treatment medicine abundanter.
Characteristics according to ranolazine preferably are prepared into slow releasing preparation with ranolazine, run into many difficulties but ranolazine is prepared into slow releasing preparation, and as the slow release instability, fluctuation is big, and adjuvant is difficult to select, preparation instability, the easy moisture absorption etc.
Ranolazine sustained release tablets provided by the invention is selected a kind of new formulation for use, has solved the problems referred to above.
Summary of the invention:
The invention provides a kind of ranolazine new formulation, it is characterized in that, comprise no more than 50wt% ranolazine and at least a 1-20wt% low viscosity pH dependent/non-dependent binding agent and one or more 1-20wt% high viscositys pH dependent/non-dependent binding agent.
Wherein low viscosity pH dependent/non-dependent binding agent is: hypromellose
60RT5, high viscosity pH dependent/non-dependent binding agent is: hypromellose
K4M
Preparation of the present invention contains: ranolazine 5%-50%, binding agent 1-45%.Also contain filler 1-45%, antitack agent 0.5-10%, lubricant 0.5-10%.
Filler is lactose, microcrystalline Cellulose, corn starch, pre-paying starch, preferred lactose, and binding agent is a hypromellose
60RT5, hypromellose
K4M, 30 POVIDONE K 30 BP/USP 30, antitack agent is a Pulvis Talci, lubricant is magnesium stearate, stearic acid, silicon dioxide, wherein preferred magnesium stearate.
Preparation of the present invention, most preferred prescription consists of:
(1), label prescription
| Ranolazine | 500g |
| Hypromellose
K4MHypromellose
60RT5Lactose 10% 30 POVIDONE K 30 BP/ |
An amount of 20g of 150g 100g 300g |
| Make | 1000 |
(2), coating fluid prescription
| Hypromellose 60RT5 | 65g |
| Pulvis Talci titanium dioxide Macrogol 600 | 20g 25g 10g |
| 75% ethanol water | Add to 1000ml. |
The preparation method of preparation of the present invention is as follows,
1. pulverize
With ranolazine, hypromellose
K4M, hypromellose
60RT5, the lactose pulverize separately crosses 100 mesh sieves, and is standby.
2. weighing, mixing
Take by weighing above-mentioned supplementary material according to recipe quantity respectively through the double calculating inventory of checking.
3. granulate
With 10% 30 POVIDONE K 30 BP/USP, 30 ethanol solution system soft materials, to granulate with 20 screen clothes, the granule that makes should lack fine powder, does not neatly have rectangular.
4. dry
50 ± 2 ℃ temperature, in drying baker aeration-drying 2-3 hour.
5. granulate
In pelletization, excessive granule is arranged, the granulate that need sieve makes the single-size that becomes to be fit to tabletting, selects 20 mesh sieve granulate for use.
6. total mixing
Add magnesium stearate, with dried granule mix homogeneously.
7. tabletting
It is heavy to calculate the actual sheet of gained according to intermediate assay result, regulates sheet and weighs tabletting.
8. art for coating:
Take by weighing hypromellose by coating fluid prescription
6ORT5, Pulvis Talci, titanium dioxide, Macrogol 600 add 75% ethanol and stir and make its dissolving.Get the plain sheet of finished product and carry out coating, inlet temperature is 40 ℃, and coating solution sprays fast 10ml/min, and the finished product weightening finish should be about 3%.
9. pack packing back warehouse-in according to the requirement of product.
The present invention also comprises the method for quality control of preparation, the process following steps:
[character] this product is a Film coated tablets, removes whitening color or off-white color behind the coating.
It is an amount of that this product fine powder is got in [discriminating] (1), and accurate the title decides, and adds methanol and makes the solution that contains 80 μ g among every 1ml approximately, measures according to ultraviolet visible spectrophotometry (two appendix IVA of Chinese Pharmacopoeia version in 2005), should absorption maximum be arranged at the wavelength place of 271 ± 2nm.
(2) in the chromatogram that writes down under the assay item, the retention time of need testing solution main peak should be consistent with the retention time of reference substance solution main peak.
[inspection] related substance is got fine powder under the assay item, and accurate the title decides, and makes the solution that contains ranolazine 0.4mg among every 1ml with mobile phase dissolving and dilution, filters, and gets subsequent filtrate as need testing solution; Precision is measured need testing solution 1ml, puts in the 100ml measuring bottle, adds mobile phase and is diluted to scale, in contrast solution; Get contrast solution 20 μ l, inject chromatograph of liquid, regulate detection sensitivity, the peak height that makes the main constituent chromatographic peak is a monitor full scale 20%～30%.Precision is measured contrast solution and each 20 μ l of need testing solution again, injects chromatograph of liquid respectively, and the record chromatogram is to 3 times of main constituent peak retention time.As showing impurity peaks, the summation of each impurity peak area must not be greater than 1.5 times (1.5%) of contrast solution main peak area in the test sample chromatogram, and the peak area of single unknown impuritie must not be greater than 1/2 (0.5%) of contrast solution main peak area.
Release is got this product, according to drug release determination method (two appendix XD first methods of Chinese Pharmacopoeia version in 2005), adopt the device of dissolution method (two appendix XC of Chinese Pharmacopoeia version in 2005) first method, 900ml is a release medium with hydrochloric acid (9 → 1000), rotating speed is that per minute 100 changes, operation in accordance with the law.Through 1,4 and 10 hour, get solution 10ml (and the release medium of replenishing the equal volume uniform temp immediately) respectively, filter, precision is measured subsequent filtrate 5.0ml, 2.0ml respectively, 2.0ml puts in the 10ml measuring bottle, add hydrochloric acid (9 → 1000) and be diluted to scale, shake up,, measure absorbance at 271nm wavelength place according to ultraviolet visible spectrophotometry (two appendix IVA of Chinese Pharmacopoeia version in 2005); It is an amount of that precision takes by weighing the ranolazine reference substance in addition, makes the solution that contains ranolazine 110 μ g among every 1ml approximately with the hydrochloric acid solution dilution, and product solution is measured its absorbance with method in contrast, calculates burst size.Every burst size of this product at 1 hour, 4 hours, 10 hours should be respectively less than labelled amount 30%, more than the 45%-65% and 75% of labelled amount, should be up to specification.
Other should meet every regulation relevant under the tablet item (two appendix IA of Chinese Pharmacopoeia version in 2005).
[assay] measured according to high performance liquid chromatography (two appendix VD of Chinese Pharmacopoeia version in 2005).
Chromatographic condition and system suitability test are filler with octadecylsilane chemically bonded silica; With methanol-acetonitrile-acetum (the 5ml glacial acetic acid adds water to 1000ml, adds the 3ml triethylamine) (25: 35: 40) (regulating pH to 6.6 with ammonia) is mobile phase, and the detection wavelength is 230nm, and number of theoretical plate calculates by the ranolazine peak and is not less than 3000.
Algoscopy is got 20 of this product, and accurate the title decided porphyrize, precision takes by weighing fine powder an amount of (being equivalent to ranolazine 20mg approximately), puts in the 50ml measuring bottle, adds that mobile phase is ultrasonic to be made dissolving and be diluted to scale, shake up, filter, precision is measured subsequent filtrate 10ml, puts in the 50ml measuring bottle, add mobile phase and be diluted to scale, shake up, precision is measured 20 μ l and is injected chromatograph of liquid, the record chromatogram.It is an amount of that other gets the ranolazine reference substance, and accurate the title decides, and dissolves also quantitatively dilution with mobile phase and make the solution that contains 80 μ g among every 1ml approximately, with method mensuration, presses external standard method with calculated by peak area, promptly.
Prescription of the present invention is that the screening process that obtains through screening is as follows:
We determine that with reference to the Ranexa (ranolazine sustained release tablets) that CV Therapeutics company produces this product specification is 500mg, has carried out the research to this product.
The prescription screening process: ranolazine is water insoluble, be soluble in the hydrochloric acid solution of 0.1mol/L, for drug slow is discharged, keep effective blood drug concentration in a long time, suppressing this product simultaneously releases the prominent of gastric, reach therapeutic purposes,, select sustained-release matrix material hypromellose commonly used for use according to present domestic production reality.Spread in Digestive system at gastrointestinal tract inner surface medicine the oral back of this product, reaches the effective blood drug level of treatment, meets aqueous medium simultaneously, at unilateral formation gel layer, stops medicine to be dashed forward and release.Prolongation along with the time, gel layer thickens, further stop the release of medicine, and, show the phenomenon that fast earlier back steadily discharges, so that keep effective blood drug concentration in a long time along with the corrosion of skeleton, reduce medicining times, make things convenient for patient's medication, reduce toxic and side effects, prevent blood concentration fluctuation.Therefore release profiles is measured, as primary investigation index.According to the requirement under two middle tablet general rule items of Chinese Pharmacopoeia version in 2005, plain sheet mode of appearance, friability and mobility of particle as evaluation index, are carried out prescription screening simultaneously.
(1), the screening of skeleton
At first fixedly the consumption of hypromellose is 300mg, investigates three different model (K of hypromellose
100M, K
15M, K
4M) influence that plain sheet is discharged.Select lactose as filler, designed prescription 1, prescription 2, prescription 3, manufacture experimently 50.The results are shown in Table 1
The screening of table 1 skeleton
Getting prescription 1, prescription 2, prescription 3 carries out release profiles and measures
| Prescription 1 | |
Prescription 3 | |
| Ranolazine hypromellose K 4MHypromellose K 15MHypromellose K 100MLactose 75% ethanol water magnesium stearate | 25g 15g--an amount of 1.0g of 15g | An amount of 1.0g of 25g-15g-15g | 25g--an amount of 1.0g of 15g 15g |
1. detect the selection of wavelength: according to the measurement result of ranolazine raw material, ranolazine has absorption maximum at the 271nm place, and absorbance is suitable, measures so we are chosen in 271nm wavelength place.
2. adjuvant interference test: being chosen in 271nm wavelength place does not have the interferential adjuvant of absorption such as hypromellose, polyvidone, lactose, magnesium stearate, microcrystalline Cellulose etc., by certain proportioning, add in the measuring bottle, measure absorbance at 271nm wavelength place according to UV-VIS spectrophotometry (two appendix IVA of Chinese Pharmacopoeia version in 2005).The result shows that adjuvant is almost noiseless at 271nm wavelength place.
3. filter membrane interference test: get the about 22mg of ranolazine raw material, adding 0.1mol/L hydrochloric acid makes and contains 110 μ g ranolazine solution among every ml, measure absorbance according to UV-VIS spectrophotometry (two appendix IVA of Chinese Pharmacopoeia version in 2005), other gets 0.45 μ m moisture film and filters, measure with method, the result shows this product solution behind water film filtering, and absorbance does not have significant change.
4. dissolution medium is selected: because ranolazine slightly soluble in the phosphate buffer of pH=6.8, insoluble in water, and this product specification is bigger, selecting water and phosphate is that 900ml can't satisfy sink conditions as the release medium volume, external simultaneously listing kind selects 0.1mol/L hydrochloric acid as release medium, so we also select 0.1mol/L hydrochloric acid to measure.
5. alr mode is selected: because this product is the hydrophilic gel slow releasing tablet, soak time is long, and slice, thin piece is floating easily.If adopt oar rule slice, thin piece off-position unfixing, influence measurement result, measure so select Chinese Pharmacopoeia two appendix XC first methods in 2005 to change the basket method.Measurement result sees Table 2
Table 2 prescription 1-3 release profiles is measured
| 1h | 2h | 4h | 6h | 8h | 10h | 12h | |
| Prescription 1 |
12.0％ 9.8％ 9.6％ | 24.7％ 19.9％ 18.4％ | 42.8％ 33.4％ 29.1％ | 55.6％ 46.3％ 38.1％ | 65.2％ 54.9％ 46.1％ | 71.7％ 61.4％ 52.8％ | 76.9％ 66.7％ 61.2％ |
Results of screening shows that along with the viscosity increase of hypromellose, release rate of drugs is slack-off.When selecting K for use
4MThe time, release rate of drugs is than k
15MAnd K
100MHurry up, but at 8h accumulative total burst size＜80%.
Consider to add low viscous hypromellose
60RT5With hypromellose
K4MCoupling, fixedly the skeleton amount is 300mg, regulates hypromellose
60RT5With hypromellose
K4MProportioning, designed the prescription 4, the prescription 5, the prescription 6, become 50.The results are shown in Table 3
The screening of table 3 prescription 4-6
| |
Prescription 5 | |
|
| The ranolazine hypromellose K4MHypromellose 60RT5Lactose 75% ethanol water magnesium stearate | An amount of 1.0g of 25g 10g 5g 15g | An amount of 1.0g of 25g 5g 10g 15g | An amount of 1.0g of 25g 7.5g 7.5g 15g |
Getting prescription 4, prescription 5, prescription 6 carries out release profiles and measures.The results are shown in Table 4
Table 4 prescription 4-6 release profiles is measured
| 1h | 2h | 4h | 6h | 8h | 10h | 12h |
| |
14.2％ 35.3％ 18.9％ | 24.6％ 47.6％ 33.5％ | 41.7％ 66.6％ 52.2％ | 58.5％ 81.2％ 67.4％ | 68.9％ 90.8％ 79.8％ | 77.0％ 96.6％ 85.3％ | 79.5％ 98.2％ 89.3％ |
Above measurement result shows, selects hypromellose
60RT5With hypromellose
K4MCoupling, skeleton total amount are 300mg, hypromellose
60RT5With hypromellose
K4MRatio be that 1: 1 o'clock release profiles is comparatively desirable, both can effectively suppress first prominent releasing, again at 10h burst size＞80%.
(2), the screening of wetting agent
Though prescription 6 release profiles are comparatively desirable, find that in the process of granulating the soft material that makes is clamminess, the difficulty of sieving, Ya Zhi plain sheet is unilateral coarse simultaneously.Analyzing reason is owing to contain a large amount of hypromelloses in the prescription, meets waterishlogging and glues, so consider to replace 75% ethanol water as wetting agent with the ethanol solution of 30 POVIDONE K 30 BP/USP 30.
To write out a prescription 6, selecting the concentration of 30 POVIDONE K 30 BP/USP 30 ethanol solutions is 0,5%, 10% 3 level.Design prescription 7, prescription 8, prescription 9, made 50.The results are shown in Table 5
The screening of table 5 wetting agent
| Prescription 7 | |
Prescription 9 | |
| The ranolazine hypromellose
K4MHypromellose
60RT5Lactose dehydrated alcohol 5% 30 |
25g 7.5g 7.5g 15g is an amount of--1.0g | 25g 7.5g 7.5g 15g-an amount of-1.0g | 25g 7.5g 7.5g 15g--an amount of 1.0g |
1. mobile the investigation
Measure the angle of repose of prescription 7-9 respectively, the results are shown in Table 6
Table 6 check result angle of repose
| The prescription number | Prescription 7 | |
Prescription 9 |
| Angle of repose | 33° | 32° | 30° |
2. friability inspection
Because this product is a coated tablet, so also should check the friability (checking according to two appendix XG of Chinese Pharmacopoeia version in 2005 tablet friability inspection technique) of plain sheet, the results are shown in Table 7
The check result of table 7 friability
| The prescription number | Prescription 7 | |
Prescription 9 |
| Friability | 1.2 | 0.5 | 0.25 |
Above measurement result shows that 9 results that write out a prescription are ideal, and the particle integrity that makes, plain sheet smooth surface, and molding is better.Selecting prescription 9 to carry out release profiles measures.The results are shown in Table 8
Table 8 prescription 9 release profiles measurement results
| 1h | 2h | 4h | 6h | 8h | 10h | 12h | |
| Prescription 9 | 12.7％ | 23.9％ | 41.7％ | 54.7％ | 65.6％ | 73.1％ | 78.6％ |
The release profiles of prescription 9 is compared with prescription 6, very big decline is arranged, at 10h release＜80%.Analyzing reason, should be to contain 30 pairs of drug releases of 30 POVIDONE K 30 BP/USP in the wetting agent to have played retarding action.According to the consumption of wetting agent, calculating every increases the about 50mg of 30 POVIDONE K 30 BP/USP 30 consumptions.
(3), continue the skeleton screening
Because the 30 POVIDONE K 30 BP/USP 30 in the wetting agent also plays the retarding action to medicine, be 250mg so reduce the skeleton amount, reduce hypromellose respectively
60RT5With hypromellose
K4MEach 50mg has designed prescription 10, prescription 11, makes 50.The results are shown in Table 9
The screening of table 9 prescription 10-11
| |
Prescription 11 | |
| The ranolazine hypromellose K4MHypromellose 60RT5 | 25g 7.5g 5g | 25g 5g 7.5g |
| |
An amount of 1.0g of 15g | An amount of 1.0g of 15g |
1. mobile the investigation
Measure the angle of repose of prescription 10-11 respectively, the results are shown in Table 10
Table 10 prescription 10-11 check result angle of repose
| The | Prescription | 10 | Prescription 11 |
| Angle of repose | 33° | 32° |
2. friability inspection
Check the friability (checking) of plain sheet, the results are shown in Table 11 according to two appendix XG of Chinese Pharmacopoeia version in 2005 tablet friability inspection technique
The check result of table 11 prescription 10-11 friability
| The | Prescription | 10 | Prescription 11 |
| Friability | 0.26 | 0.27 |
Above measurement result shows that prescription 10 and prescription 11 be basically identical as a result, and the particle integrity that makes, plain sheet smooth surface, and molding is better.Prescription 10 and prescription 11 carry out release profiles and measure relatively.The results are shown in Table 12
Table 12 prescription 10-11 release profiles is measured
| 1h | 2h | 4h | 6h | 8h | | 12h | |
| Prescription | |||||||
| 10 prescriptions 11 | 21.6％ 36.3％ | 33.6％ 50.2％ | 53.2％ 66.3％ | 67.7％ 79.6％ | 81.3％ 89.6％ | 91.1％ 97.8％ | 97.7％ 98.1％ |
Measure according to top release profiles and to show that the 10 release profiles ideals of writing out a prescription can effectively suppress prominent and release, and at 10h burst size＞85%, and write out a prescription and 10 make particle integrity, plain sheet molding is better.So select prescription 10 as the optimum prescription of plain sheet, carry out art for coating research.
(4), coating prescription and technology
Selecting prescription 10 is plain tablet recipe, amplifies 300, carries out art for coating research.The results are shown in Table 13, table 14
Table 13 prescription 10 amplifies
| |
|
| The ranolazine hypromellose
K4MHypromellose
60RT5Lactose 10% 30 |
An amount of 6g of 150g 45g 30g 90g |
The prescription of table 14 coating solution is formed
| Hypromellose 60rt5 | 65g |
| Macrogol 600 Pulvis Talci titanium dioxide 75% alcoholic solution | 10g 20g 25g adds to 1000ml |
Operating procedure: 40 ℃ of coating inlet temperature, coating solution sprays fast 10ml/min, and its release profiles is checked in coating weightening finish 3.1%, and the result is as seeing Table 15
Release profiles measurement result behind table 15 prescription 10 coatings
| 1h | 2h | 4h | 6h | 8h | | 12h | |
| Prescription | |||||||
| 10 | 22.0％ | 33.7％ | 54.8％ | 65.1％ | 79.8％ | 93.5％ | 97.5％ |
By above result as can be known behind this prescription coating release profiles smoother, at 10h＞85%.So our label is selected prescription 10 for use, bag film-coat weightening finish 3%, amplifying 3 batches of lot numbers is 060302,060304,060306, investigates its stability.
Three, trial-manufacture of sample
Produce 3 batch samples, 3000 every crowd according to prescription 10 plain tablet recipes and definite coating prescription and technology amplification.The results are shown in Table 16
Table 16 three batch sample trial results
| Lot number | Plan trial-production number | Actual trial-production number | Yield rate |
| 060302 batch 060304 batch 060306 batch | 3,000 3,000 3000 | 2,748 2,769 2757 | 91.6 92.3 91.9 |
Four, influence factor's test
1, the influence factor of 4500LX ± 500LX illumination condition test:
Get 060302 batch of ranolazine sustained release tablets and place glass dish, under the illumination of 4500LX ± 500LX, placed 10 days, in 0,
5, sampling in 10 days detects, and testing result sees Table 17
Table 174500LX ± 500LX illumination effect factorial experiments result
| Time (my god) | 0 | 5 | 10 | |
| Character | The white film garment piece | The white film garment piece | The white film garment piece | |
| Release (%) | 1h | 22.0 | 21.4 | 21.0 |
| 4h | 55.8 | 53.5 | 54.2 | |
| 10h | 96.3 | 93.3 | 93.2 | |
| Related substance (%) | Single impurity (%) | 0.27 | 0.34 | 0.35 |
| Total impurities (%) | 0.47 | 0.52 | 0.53 | |
| Content (%) | 99.9 | 99.4 | 99.7 | |
2, temperatures involved factorial experiments:
Get 060302 batch of ranolazine sustained release tablets and place glass dish, placed 10 days in 60 ℃ ± 2 ℃ calorstat, detect in sampling in 0,5,10 day, testing result sees Table 18
Table 1860 ℃ ± 2 ℃ of temperatures involved factorial experiments results
| Time (my god) | 0 | 5 | 10 | |
| Character | The white film garment piece | The white film garment piece | The white film garment piece | |
| Release (%) | 1h | 22.0 | 20.8 | 20.6 |
| 4h | 55.8 | 55.3 | 53.0 | |
| 10h | 96.3 | 92.7 | 92.5 | |
| Related substance (%) | Single impurity (%) | 0.27 | 0.29 | 0.35 |
| Total impurities (%) | 0.47 | 0.44 | 0.53 | |
| Content (%) | 99.9 | 99.7 | 99.3 |
3, high humidity influence factor result of the test
The ranolazine sustained release tablets of getting 060302 batch places glass dish, at 25 ℃ of relative humidity 92.5% ± 5% (KNO
3Saturated solution) placed 10 days in the calorstat, detect in sampling in 0,5,10 day, testing result sees Table 19
Table 1992.5% ± 5% high humidity influence factor result of the test
| Time (my god) | 0 | 5 | 10 | |
| Character | The white film garment piece | The white film garment piece | The white film garment piece | |
| Moisture absorption weightening finish (%) | 1.99 | 3.78 | ||
| Release (%) | 1h | 22.0 | 21.0 | 21.1 |
| 4h | 55.8 | 53.4 | 54.2 | |
| 10h | 96.3 | 93.2 | 93.3 | |
| Related substance (%) | Single impurity (%) | 0.27 | 0.33 | 0.30 |
| Total impurities (%) | 0.47 | 0.49 | 0.49 | |
| Content (%) | 99.9 | 100.1 | 99.6 | |
Above result of the test shows: this product is in 4500LX ± 500LX illumination, and is under 60 ℃ ± 2 ℃ high temperature, 92.5% ± 5% super-humid conditions, comparatively stable.This product is subjected to the influence of temperature, humidity and light less.
Through above evidence: product formulation and technology simple possible.To be packaged in 40 ℃ ± 2, placement 6 months and room temperature condition were placed 6 months under the condition of relative humidity 75% through this product.The result shows that the more stable clinical medicine that meets of quality prepares requirement.
Description of drawings:
Fig. 1 compares for prescription 1-3 release profiles
Fig. 2 compares for prescription 4-6 release profiles
Fig. 3 compares for prescription 6 and 9 release profiles
Fig. 4 compares for prescription 10 and 11 release profiles
Fig. 5 is that release profiles is measured behind prescription 10 coatings
The specific embodiment:
Further specify the present invention by the following examples, but not as limitation of the present invention:
Embodiment 1
(1), label prescription
| Ranolazine | 500g |
| Hypromellose
K4MHypromellose
60RT5Lactose 10% 30 |
An amount of 20g of 150g 100g 300g |
| Make | 1000 |
(2), coating fluid prescription
| Hypromellose 60RT5Pulvis Talci titanium dioxide Macrogol 600 | 65g 20g 25g 10g |
| 75% ethanol water | Add to 1000ml. |
Preparation method,
1 pulverizes
With ranolazine, hypromellose
K4M, hypromellose
60RT5, the lactose pulverize separately crosses 100 mesh sieves, and is standby.
2. weighing, mixing
Take by weighing above-mentioned supplementary material according to recipe quantity respectively through the double calculating inventory of checking.
3. granulate
With 10% 30 POVIDONE K 30 BP/USP, 30 ethanol solution system soft materials, to granulate with 20 screen clothes, the granule that makes should lack fine powder, does not neatly have rectangular.
4. dry
50 ± 2 ℃ temperature, in drying baker aeration-drying 2-3 hour.
5. granulate
In pelletization, excessive granule is arranged, the granulate that need sieve makes the single-size that becomes to be fit to tabletting, selects 20 mesh sieve granulate for use.
6. total mixing
Add magnesium stearate, with dried granule mix homogeneously.
7. tabletting
It is heavy to calculate the actual sheet of gained according to intermediate assay result, regulates sheet and weighs tabletting.
8. art for coating:
Take by weighing hypromellose by coating fluid prescription
60RT5, Pulvis Talci, titanium dioxide, Macrogol 600 add 75% ethanol and stir and make its dissolving.Get the plain sheet of finished product and carry out coating, inlet temperature is 40 ℃, and coating solution sprays fast 10ml/min, and the finished product weightening finish should be about 3%.
9. pack packing back warehouse-in according to the requirement of product.
Claims (8)
1. a ranolazine formulation that continues to discharge is characterized in that, said preparation comprises no more than 50wt% ranolazine and at least a 1-20wt% low viscosity pH dependent/non-dependent binding agent and one or more 1-20wt% high viscositys pH dependent/non-dependent binding agent.
2. the preparation of claim 1 is characterized in that, wherein low viscosity pH dependent/non-dependent binding agent is: hypromellose
60RT5, high viscosity pH dependent/non-dependent binding agent is: hypromellose
K4M
3. the preparation of claim 1 is characterized in that, contains: ranolazine 5%-50%, binding agent 1-45%.
4. the preparation of claim 3 is characterized in that, also contains filler 1-45%, antitack agent 0.5-10%, lubricant 0.5-10%.
5. the preparation of claim 4 is characterized in that, filler is lactose, microcrystalline Cellulose, corn starch, pre-paying starch, and antitack agent is a Pulvis Talci, and lubricant is magnesium stearate, stearic acid, silicon dioxide.
6. the preparation of claim 1 is characterized in that, its prescription consists of:
(1), label prescription
(2), coating fluid prescription
7. the preparation method of the preparation of claim 1 is characterized in that,
1. pulverize
With ranolazine, hypromellose
K4M, hypromellose
60RT5, the lactose pulverize separately crosses 100 mesh sieves, and is standby,
2. weighing, mixing
Take by weighing above-mentioned supplementary material according to recipe quantity respectively through the double calculating inventory of checking,
3. granulate
With 10% 30 POVIDONE K 30 BP/USP, 30 ethanol solution system soft materials, granulate with 20 screen clothes, the granule that makes should lack fine powder, neatly do not have rectangular,
4. dry
50 ± 2 ℃ temperature, in drying baker aeration-drying 2-3 hour,
5. granulate
In pelletization, excessive granule is arranged, the granulate that need sieve makes the single-size that becomes to be fit to tabletting, selects 20 mesh sieve granulate for use,
6. total mixing
Add magnesium stearate, with dried granule mix homogeneously,
7. tabletting
It is heavy to calculate the actual sheet of gained according to intermediate assay result, and regulate sheet and weigh, tabletting,
8. art for coating:
Take by weighing hypromellose by coating fluid prescription
6ORT5, Pulvis Talci, titanium dioxide, Macrogol 600 add 75% ethanol and stir and make its dissolving, gets the plain sheet of finished product and carry out coating, inlet temperature is 40 ℃, coating solution sprays fast 10ml/min, the finished product weightening finish should be about 3%,
9. pack packing back warehouse-in according to the requirement of product.
8. the method for quality control of the preparation of claim 1 is characterized in that, the process following steps:
[character] this product is a Film coated tablets, removes whitening color or off-white color behind the coating,
It is an amount of that this product fine powder is got in [discriminating] (1), and accurate the title decides, and adds methanol and makes the solution that contains 80 μ g among every 1ml approximately, measures according to ultraviolet visible spectrophotometry (two appendix IV of Chinese Pharmacopoeia version in 2005 A), should absorption maximum be arranged at the wavelength place of 271 ± 2nm,
(2) in the chromatogram that writes down under the assay item, the retention time of need testing solution main peak should be consistent with the retention time of reference substance solution main peak,
[inspection] related substance is got fine powder under the assay item, and accurate the title decides, and makes the solution that contains ranolazine 0.4mg among every 1ml with mobile phase dissolving and dilution, filters, and gets subsequent filtrate as need testing solution; Precision is measured need testing solution 1ml, puts in the 100ml measuring bottle, adds mobile phase and is diluted to scale, in contrast solution; Get contrast solution 20 μ l, inject chromatograph of liquid, regulate detection sensitivity, the peak height that makes the main constituent chromatographic peak is a monitor full scale 20%～30%, precision is measured contrast solution and each 20 μ l of need testing solution again, inject chromatograph of liquid respectively, the record chromatogram is to 3 times of main constituent peak retention time, in the test sample chromatogram as show impurity peaks, the summation of each impurity peak area must not be greater than 1.5 times of contrast solution main peak area, (1.5%), the peak area of single unknown impuritie must not be greater than 1/2 of contrast solution main peak area, (0.5%)
Release is got this product, according to drug release determination method (two appendix XD first methods of Chinese Pharmacopoeia version in 2005), adopt the device of dissolution method (two appendix XC of Chinese Pharmacopoeia version in 2005) first method, 900ml is a release medium with hydrochloric acid (9 → 1000), rotating speed is that per minute 100 changes, operation in accordance with the law, through 1,4 and 10 hours, get solution 10ml (and the release medium of replenishing the equal volume uniform temp immediately) respectively, filter, precision is measured subsequent filtrate 5.0ml respectively, 2.0ml, 2.0ml put in the 10ml measuring bottle, add hydrochloric acid (9 → 1000) and be diluted to scale, shake up,, measure absorbance at 271nm wavelength place according to ultraviolet visible spectrophotometry (two appendix IVA of Chinese Pharmacopoeia version in 2005); It is an amount of that precision takes by weighing the ranolazine reference substance in addition, make the solution that contains ranolazine 110 μ g among every 1ml approximately with the hydrochloric acid solution dilution, product solution in contrast, measure its absorbance with method, calculate burst size, every burst size of this product at 1 hour, 4 hours, 10 hours should be respectively less than labelled amount 30%, more than the 45%-65% and 75% of labelled amount, should be up to specification
Other should meet every regulation relevant under the tablet item (two appendix IA of Chinese Pharmacopoeia version in 2005),
[assay] measured according to high performance liquid chromatography (two appendix VD of Chinese Pharmacopoeia version in 2005),
Chromatographic condition and system suitability test are filler with octadecylsilane chemically bonded silica; With methanol-acetonitrile-acetum (the 5ml glacial acetic acid adds water to 1000ml, adds the 3ml triethylamine) (25: 35: 40) (regulating pH to 6.6 with ammonia) is mobile phase, and the detection wavelength is 230nm, and number of theoretical plate calculates by the ranolazine peak and is not less than 3000,
Algoscopy is got 20 of this product, the accurate title, decide, porphyrize, and precision takes by weighing fine powder an amount of (being equivalent to ranolazine 20mg approximately), put in the 50ml measuring bottle, add that mobile phase is ultrasonic to be made dissolving and be diluted to scale, shake up, filter, precision is measured subsequent filtrate 10ml, put in the 50ml measuring bottle, add mobile phase and be diluted to scale, shake up, precision is measured 20 μ l and is injected chromatograph of liquid, the record chromatogram, it is an amount of that other gets the ranolazine reference substance, and accurate the title, decide, make the solution that contains 80 μ g among every 1ml approximately with mobile phase dissolving and quantitative dilution, measure with method, press external standard method with calculated by peak area, promptly.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200710301262A CN100581547C (en) | 2007-12-18 | 2007-12-18 | Ranolazine sustained release tablets |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200710301262A CN100581547C (en) | 2007-12-18 | 2007-12-18 | Ranolazine sustained release tablets |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101176723A true CN101176723A (en) | 2008-05-14 |
| CN100581547C CN100581547C (en) | 2010-01-20 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200710301262A Expired - Fee Related CN100581547C (en) | 2007-12-18 | 2007-12-18 | Ranolazine sustained release tablets |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105616370A (en) * | 2014-11-27 | 2016-06-01 | 四川海思科制药有限公司 | Ranolazine sustained release tablet medicine composition and preparation method thereof |
| WO2017001669A1 (en) | 2015-07-02 | 2017-01-05 | Interquim, S.A. | Ranolazine multiple compressed tablets |
| CN107213131A (en) * | 2015-09-08 | 2017-09-29 | 深圳信立泰药业股份有限公司 | Packaging technique for treating angiocardiopathy solid pharmaceutical preparation |
| WO2018001582A1 (en) | 2016-06-30 | 2018-01-04 | Interquim, S.A. | Ranolazine multiple compressed tablets |
-
2007
- 2007-12-18 CN CN200710301262A patent/CN100581547C/en not_active Expired - Fee Related
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105616370A (en) * | 2014-11-27 | 2016-06-01 | 四川海思科制药有限公司 | Ranolazine sustained release tablet medicine composition and preparation method thereof |
| WO2017001669A1 (en) | 2015-07-02 | 2017-01-05 | Interquim, S.A. | Ranolazine multiple compressed tablets |
| CN107213131A (en) * | 2015-09-08 | 2017-09-29 | 深圳信立泰药业股份有限公司 | Packaging technique for treating angiocardiopathy solid pharmaceutical preparation |
| WO2018001582A1 (en) | 2016-06-30 | 2018-01-04 | Interquim, S.A. | Ranolazine multiple compressed tablets |
Also Published As
| Publication number | Publication date |
|---|---|
| CN100581547C (en) | 2010-01-20 |
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