CN100382794C - Dispersed tablet of tartaric acid tolterodine tartrate - Google Patents
Dispersed tablet of tartaric acid tolterodine tartrate Download PDFInfo
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- CN100382794C CN100382794C CNB2004100573635A CN200410057363A CN100382794C CN 100382794 C CN100382794 C CN 100382794C CN B2004100573635 A CNB2004100573635 A CN B2004100573635A CN 200410057363 A CN200410057363 A CN 200410057363A CN 100382794 C CN100382794 C CN 100382794C
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- tolterodine tartrate
- dispersed
- tablet
- tolterodine
- tartrate
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- YYSCJLLOWOUSHH-UHFFFAOYSA-N 4,4'-disulfanyldibutanoic acid Chemical compound OC(=O)CCCSSCCCC(O)=O YYSCJLLOWOUSHH-UHFFFAOYSA-N 0.000 title claims abstract description 43
- 229960003553 tolterodine tartrate Drugs 0.000 title claims abstract description 43
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 title claims 4
- 235000002906 tartaric acid Nutrition 0.000 title 1
- 239000011975 tartaric acid Substances 0.000 title 1
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 36
- 239000000654 additive Substances 0.000 claims abstract 4
- 239000007919 dispersible tablet Substances 0.000 claims description 19
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- BCGWQEUPMDMJNV-UHFFFAOYSA-N imipramine Chemical compound C1CC2=CC=CC=C2N(CCCN(C)C)C2=CC=CC=C21 BCGWQEUPMDMJNV-UHFFFAOYSA-N 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The present invention belongs to a medicinal technology, particularly to a dispersed tablet of tolterodine tartrate. The dispersed tablet of tolterodine tartrate contains main components of tolterodine tartrate and disintegrating agents and auxiliary additives, wherein the disintegrating agents are dispersed tablet type disintegrating agents commonly used for preparing dispersed tablets, and the auxiliary additives are dispersed tablet type additives commonly used for preparing the dispersed tablets. The dispersed tablet overcomes the defects that the slow disintegration of a conventional tolterodine tartrate preparation results in slow dissolution, and consequently, sufficient absorption and curative effects of medicine are influenced, etc. The dispersed tablet of tolterodine tartrate is convenient for old patients and young patients to take, has the advantages of stable preparation, fast absorption, high biological availability and few adverse reactions, and is used as a drug for curing frequent micturition, urgent micturition and urinary incontinence.
Description
Affiliated technical field
The invention belongs to medical technology, particularly a kind of Tolterodine tartrate tablet formulation.
Background technology
In recent years, with the quickening pace of modern life, operating pressure increases, aging society crowd's expansion, and urine incontinence is more and more, and the patient is rejuvenation more and more.Estimate that according to the relevant personnel of The World Health Organization (WHO) the whole world has 10～15% middle age (the right side of fifty) and 40～70% old peoples to be subjected to the puzzlement of urinary incontinence in various degree approximately, the women is 2 times of male.Owing to the excited and full stage of bladder excessive is finished the frequent micturition that the uncontrollable contraction of urine flesh causes, urgent micturition or urge incontinence have had a strong impact on people's live and work.Therefore, suitable exercise, reasonably Drug therapy all is very important.
Treated in the past the bladder excessive excitement (for the most commonly encountered diseases of veteran form urinary incontinence because of) medicine mainly contain oxibutynin (oxybutynin), this medicine has been used for many years as unstable bladder treatment drug of first choice, but owing to its to M
3The selectivity of receptor is higher than M
2Receptor is better than this receptor in the bladder to the selective exclusion effect of receptor in the parotid gland, causes higher xerostomia side effect.Other drug such as propantheline bromide, hyoscyamine, flavoxate and tricyclic antidepressant imipramine, though all have the Antimuscarinic effect, all because untoward reaction, especially xerostomia make application limited.
Tolterodine tartrate is a kind of novel efficient muscarinic receptor antagonist that is used for the treatment of frequent micturition that the bladder excessive excitement causes, urgent micturition, urinary incontinence.Compare with oxibutynin, have the following advantages:
1, the xerostomia side effect is low.Tolterodine tartrate is efficient muscarinic receptor antagonist, and it is to M in the bladder
3Receptor has the high selectivity blocking-up, and to M in the parotid gland
3Receptor blocking is slight, thus the xerostomia side effect that causes because of taking medicine far below other with the curative effect medicine, the incidence rate to the severe xerostomia during Tolterodine tartrate causes under the recommended dose only is 17%, oxibutynin then is 60%.Abroad as a line medicine, as the treatment of urinary incontinence.
2, the excitation of inhibition bladder is strong, and curative effect and safety are all good.It is rapid that this product is taken post-absorption, and absorbance is higher than 77%, and with the plasma protein binding rate height, the drug action time is long.Take Tolterodine tartrate 2mg, every day 2 times, the number of micturitions that can reduce every day respectively and urinary incontinence attack times 20% and 47%, average simultaneously each voided volume increases by 22%.The drug effect and the oxibutynin of Tolterodine tartrate are suitable, but the former tolerance makes these product can be used as long-term treatment.
3, dosage is little, few side effects.This product 2mg/ sheet, one day twice, the one day a slice of being grown up, consumption is less.This product and oxibutynin compare, therapeutic equivalence, but side effect significantly is less than oxibutynin, and it takes place than being 8%:39% with oxibutynin side effect probability, is hyperactive safer, the effective medicine of treatment bladder.Simultaneously tolterodine is also safe and effective to frequently the show effect treatment of cystospasm of intractable, and adverse reaction rate has improved patient's toleration greatly far below conventional medicaments such as verapamils.
These product are by Pharmacia﹠amp; The exploitation of Upjohn company was at first gone on the market in Sweden in 1997, and go on the market in the U.S. in May, 1998, and it is first medicine that is used for the treatment of bladder control obstacle that the U.S. ratified over more than 20 year.Now should go on the market in more than 20 countries by product.Lunan Pharmacy Co. Ltd obtained Tolterodine tartrate sheet New Drug Certificate in 2000, the accurate font size of traditional Chinese medicines is: X20000614.Its specification is the 2mg/ sheet, 1～2 time on the one.
Goal of the invention
The invention provides a kind of Tolterodine tartrate tablet formulation.Ordinary preparation for Tolterodine tartrate, as ordinary tablet, its specification is the 2mg/ sheet, because of disintegrate and the slow abundant absorption that influences medicine of medicine stripping, and the corresponding patient of this product is in the majority with the old people, the situation of dysphagia when occurring taking often, simultaneously in therapeutic process, remain in slight xerostomia, dyspepsia is felt sick, untoward reaction such as vomiting.The objective of the invention is to overcome above-mentioned shortcoming.
Technical scheme
Tolterodine tartrate dosage form of the present invention is a tablet formulation, and principal agent composition Tolterodine tartrate is optimized for 0.1～20mg, more is optimized for 1～8mg, and optimum turns to 2mg.
Disintegrating agent is the tablet formulation disintegrating agent commonly used of preparation tablet formulation, and the content of disintegrating agent is optimized for 1～80% among the present invention, more is optimized for 10～30%.Optimization principles: guaranteeing that the consumption of disintegrating agent is few under the fast prerequisite of the rapid stripping of disintegrate of the present invention.
The invention advantage
The advantage of Tolterodine tartrate tablet formulation of the present invention is further to improve the principal agent dissolubility, promptly meet water and can form even viscosity suspension rapidly, can and disperse in the rapid disintegrate of gastrointestinal tract, the medicine distribution area is increased, absorption point increases, avoid ordinary preparation too high in the gastrointestinal tract local drug concentration, shortcomings such as stimulating gastrointestinal mucosa, reduce untoward reaction, improve patient adaptability, have taking convenience, absorb characteristics such as fast, bioavailability height, and make things convenient for old man and child patient to take, as a kind of treatment frequent micturition, the medicine of urgent micturition, urinary incontinence.
Through a large amount of experimentatioies, determined the final technology preparation of Tolterodine tartrate dispersible tablet, and confirmed that in animal experiment the present invention really has above-mentioned advantage.In test, we have selected multiple medicinal disintegrating agent with disintegration properties to compare, and find that not all disintegrating agent that can be used for dispersible tablet can both be applied to the present invention.The technical barrier that the present invention solves, also be technical characterictic is the selection to disintegrating agent, finally selected disintegrating agent and be in the disintegrating agents such as starch, pregelatinized Starch, carboxymethyl starch sodium, hydroxypropyl cellulose, crospolyvinylpyrrolidone, cross-linking sodium carboxymethyl cellulose, hydroxypropyl starch, carboxymethylcellulose calcium, sodium alginate, hydroxy acid cellulose, sodium carboxymethyl cellulose, methacrylic acid, divinylbenzene copolyesters, IRP-88, guar gum, Herba Xanthii glue, glucosan, carboxymethylcellulose calcium one or more.
In research process, investigated the preparation technology of Tolterodine tartrate dispersible tablet, determined that its preparation technology is the pharmaceutic adjuvant mix homogeneously in will writing out a prescription earlier, then with the Tolterodine tartrate of recipe quantity and its by the equivalent method mixing that progressively increases, a uniform mixing powder, granulate then, oven dry, granulate adds the lubricant mixing, tabletting, promptly.
Description of drawings
Fig. 1: the external stripping curve of prescription A: Fig. 2: the external stripping curve of prescription B: Fig. 3: the external stripping curve of prescription C: Fig. 4: the external stripping curve of prescription D: Fig. 5: the external stripping curve of prescription E: Fig. 6: the external stripping curve of prescription F
The specific embodiment
Embodiment: (prescription is in 1000 inventorys)
Eight kinds of concrete prescriptions:
Prescription A:
Tolterodine tartrate 0.1g
Microcrystalline Cellulose (filler) 0.5g
Crospolyvinylpyrrolidone (disintegrating agent) 47g
4%PVP
K30Aqueous solution (binding agent) 50g
Magnesium stearate (lubricant) 0.4g
Preparation technology: principal agent is crossed 160 mesh sieves, and filler, disintegrating agent are crossed 100 mesh sieves, takes by weighing filler, the disintegrating agent mix homogeneously of recipe quantity, then with the principal agent of recipe quantity and its by the equivalent method mixing that progressively increases, add binding agent and granulate in right amount, dry back adds recipe quantity lubricant mixing, and tabletting promptly.Dispersible tablet is limited to 2.7min when disperseing.
Prescription B:
Tolterodine tartrate 0.5g
Microcrystalline Cellulose (filler) 91g
Crospolyvinylpyrrolidone (disintegrating agent) 5g
5%PVP
K30Aqueous solution (binding agent) 60g
Magnesium stearate (lubricant) 0.5g
Preparation technology is with prescription A.Dispersible tablet is limited to 2.1min when disperseing.
Prescription C
Tolterodine tartrate 1g
Microcrystalline Cellulose (filler) 84g
Carboxymethyl starch sodium (disintegrating agent) 10g
5%PVP
K30Ethanol solution (binding agent) 80g
Magnesium stearate (lubricant) 1g
Preparation technology is with prescription A.Dispersible tablet is limited to 1.6min when disperseing.
Prescription D:
Tolterodine tartrate 2g
Lactose (filler) 73g
Carboxymethyl starch sodium (disintegrating agent) 20g
5%PVP
K30Ethanol solution (binding agent) 80g
Magnesium stearate (lubricant) 1g
Preparation technology is with prescription A.Dispersible tablet is limited to 1.1min when disperseing.
Prescription E
Tolterodine tartrate 4g
Microcrystalline Cellulose (filler) 57g
Hydroxypropyl cellulose (disintegrating agent) 30g
10% starch slurry (binding agent) 80g
Magnesium stearate (lubricant) 1g
Preparation technology is with prescription A.Dispersible tablet is limited to 0.8min when disperseing.
Prescription F:
Tolterodine tartrate 8g
Microcrystalline Cellulose (filler) 43g
Hydroxypropyl cellulose (disintegrating agent) 20g
Carboxymethyl starch sodium (disintegrating agent) 20g
8%PVP
K30Aqueous solution (binding agent) 100g
Magnesium stearate (lubricant) 1g
Preparation technology: principal agent is crossed 160 mesh sieves, and filler, disintegrating agent are crossed 100 mesh sieves, takes by weighing principal agent, filler, the disintegrating agent mix homogeneously of recipe quantity, adds binding agent and granulates in right amount, and dry back adds recipe quantity lubricant mixing, and tabletting promptly.Dispersible tablet is limited to 0.6min when disperseing.
Prescription G:
Tolterodine tartrate 10g
Mannitol (filler) 24g
Hydroxypropyl cellulose (disintegrating agent) 30g
Crospolyvinylpyrrolidone (disintegrating agent) 30g
5%PVP
K30Aqueous solution (binding agent) 100g
Magnesium stearate (lubricant) 0.6g
Preparation technology is with prescription F.Dispersible tablet is limited to 0.4min when disperseing.
Prescription H:
Tolterodine tartrate 20g
Carboxymethyl starch sodium (disintegrating agent) 56g
Crospolyvinylpyrrolidone (disintegrating agent) 56g
7%PVP
K30Ethanol solution (binding agent) 100g
Magnesium stearate (lubricant) 1g
Preparation technology is with prescription F.Dispersible tablet is limited to 0.2min when disperseing.
The zoopery of Tolterodine tartrate dispersible tablet
Animal body giving drugs into nose of the present invention is as follows for the dynamic experiment method: experiment is divided into two groups, every group of 6 beagle dogs; Matched group gives Tolterodine tartrate sheet (2mg/ sheet, commodity peaceful the leading to by name of oral Lunan Pharmacy Co. Ltd
), a daily amount 1～4mg divides and takes for 1～2 time; Experimental group gives oral the present invention (prescription A～H, 2mg/ sheet) daily amount 1～4mg, divides and takes for 1～2 time; Respectively in administration after 1,2,3,4,5,6,7 hours, get the blood drug level of determination of serum Tolterodine tartrate, the result shows: matched group and experimental group all do not have marked difference at the area under the drug-time curve (AUC) of each time point, the present invention is according to a daily amount 1～4mg in prompting, divide to take for 1～2 time to reach ideal blood drug level, have excellent curative.
Tolterodine tartrate dispersible tablet dispersing uniformity and dissolution in vitro inspection
1, Tolterodine tartrate dispersible tablet dispersing uniformity is checked
The Tolterodine tartrate dispersible tablet (A～H), its dispersing uniformity experimental technique is as follows for prescription: get 2 of this product, put jolting in the 100ml water, and in 20 ℃ ± 1 ℃ water, all disintegrates and sieve in 3 minutes by No. 2.See table 1～8 for details.
2, the mensuration of Tolterodine tartrate dispersible tablet dissolution in vitro
The Tolterodine tartrate dispersible tablet (A～H), its dissolution in vitro experimental technique is as follows for prescription:
Measure according to high performance liquid chromatography (two appendix V of Chinese Pharmacopoeia version in 2000 D).Chromatographic condition and system suitability test are filler with octadecylsilane chemically bonded silica; With methanol: 0.02mol/L ammonium formate solution (regulating pH value to 3.0 with formic acid) (60: 40) be mobile phase, and flow velocity is 1.0ml/min, and the detection wavelength is 283nm, and theoretical cam curve should be not less than 2000 by the calculating of Tolterodine tartrate peak.
Getting this product, according to dissolution method (two appendix X of Chinese Pharmacopoeia version in 2000 C three therapeutic methods of traditional Chinese medicine), is solvent with 100ml water, and rotating speed is that per minute 50 changes, and operation in the time of 30 minutes, is got solution 10ml in accordance with the law, filters, and gets subsequent filtrate as need testing solution.It is an amount of that other is taken at 105 ℃ of Tolterodine tartrate reference substances that are dried to constant weight, accurate claim fixed, with water dissolution and make the solution that contains 20 μ g among every 1ml, product solution in contrast.The subsequent filtrate 20 μ l that get above-mentioned two kinds of solution inject chromatograph of liquid, and the record chromatogram is by the stripping quantity of external standard method with every of calculated by peak area.Limit is 75% of a labelled amount, should be up to specification.See table 1～8 for details.
Table 1: the cumulative in vitro dissolution of prescription A
Table 2: the cumulative in vitro dissolution of prescription B
Table 3: the cumulative in vitro dissolution of prescription C
Table 4: the cumulative in vitro dissolution of prescription D
Table 5: the cumulative in vitro dissolution of prescription E
Table 6: the cumulative in vitro dissolution of prescription F
Table 7: the cumulative in vitro dissolution of prescription G
Table 8: the cumulative in vitro dissolution of prescription H
Claims (2)
1. a Tolterodine tartrate tablet formulation is characterized in that being tablet formulation, wherein contains:
(1) Tolterodine tartrate, chemical name are (R)-N, N-diisopropyl-3-(2-hydroxy-5-methyl base phenyl)-3-phenylpropylamine L (±)-tartrate, and molecular formula is C
22H
31NOC
4H
6O
6, structural formula is:
The amount of described Tolterodine tartrate dispersible tablet mesotartaric acid tolterodine in every is 1～8mg;
(2) disintegrating agent;
(3) pharmaceutically useful auxiliary additive,
Wherein said disintegrating agent is one or more in carboxymethyl starch sodium, hydroxypropyl cellulose, the crospolyvinylpyrrolidone, and the content of disintegrating agent is 10～30%.
2. tablet formulation as claimed in claim 1 is characterized in that the amount of every described Tolterodine tartrate dispersible tablet mesotartaric acid tolterodine is 2mg.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100573635A CN100382794C (en) | 2004-08-30 | 2004-08-30 | Dispersed tablet of tartaric acid tolterodine tartrate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100573635A CN100382794C (en) | 2004-08-30 | 2004-08-30 | Dispersed tablet of tartaric acid tolterodine tartrate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1628646A CN1628646A (en) | 2005-06-22 |
| CN100382794C true CN100382794C (en) | 2008-04-23 |
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| CNB2004100573635A Expired - Fee Related CN100382794C (en) | 2004-08-30 | 2004-08-30 | Dispersed tablet of tartaric acid tolterodine tartrate |
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Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1330297C (en) * | 2005-07-04 | 2007-08-08 | 宛六一 | Tolterodine tartrate soft capsule and its preparing method |
| CN105832685A (en) * | 2016-05-25 | 2016-08-10 | 南京正科医药股份有限公司 | Tolterodine tartrate tablets |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998003067A1 (en) * | 1996-07-19 | 1998-01-29 | Gunnar Aberg | S(-)-tolterodine in the treatment of urinary and gastrointestinal disorders |
| WO2003026564A2 (en) * | 2001-09-27 | 2003-04-03 | Pharmacia Ab | Pharmaceutical compositions for the treatment of urinary disorders |
| CN1420767A (en) * | 1999-11-11 | 2003-05-28 | 法马西雅公司 | Pharmaceutical formulation contg. tolterodine and its use |
-
2004
- 2004-08-30 CN CNB2004100573635A patent/CN100382794C/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998003067A1 (en) * | 1996-07-19 | 1998-01-29 | Gunnar Aberg | S(-)-tolterodine in the treatment of urinary and gastrointestinal disorders |
| US6310103B1 (en) * | 1996-07-19 | 2001-10-30 | Bridge Pharma, Inc. | S(−)-tolterodine in the treatment of urinary and gastrointestinal disorders |
| CN1420767A (en) * | 1999-11-11 | 2003-05-28 | 法马西雅公司 | Pharmaceutical formulation contg. tolterodine and its use |
| WO2003026564A2 (en) * | 2001-09-27 | 2003-04-03 | Pharmacia Ab | Pharmaceutical compositions for the treatment of urinary disorders |
Non-Patent Citations (4)
| Title |
|---|
| 分散片的研究与应用. 陈鹰，匡长春，宋琪，汤韧，韩勇.中国药师，第4卷第1期. 2001 * |
| 分散片的研究进展. 沈岚，林晓，冯怡，徐德生.中成药，第26卷第2期. 2004 * |
| 尿失禁与尿潴留的药物治疗进展. 李明，赵久荣，刘燕.中国药师，第3卷第4期. 2000 * |
| 治疗膀胱过渡活动症的新药托特罗定. 袁宁.药学进展，第25卷第1期. 2001 * |
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| CN1628646A (en) | 2005-06-22 |
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Assignee: LUNNAN BETTER PHARMACEUTICAL Co.,Ltd. Assignor: LUNAN PHARMACEUTICAL Group Corp. Contract record no.: 2010370000513 Denomination of invention: Dispersed tablet of tartaric acid tolterodine tartrate Granted publication date: 20080423 License type: Exclusive License Open date: 20050622 Record date: 20100909 |
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Effective date of registration: 20161214 Address after: 276005 Hongqi Road, Shandong, Linyi, No. 209 Patentee after: LUNNAN BETTER PHARMACEUTICAL Co.,Ltd. Address before: 276005 Hongqi Road, Shandong, Linyi, No. 209 Patentee before: LUNAN PHARMACEUTICAL Group Corp. |
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