CN1628646A - Dispersed tablet of tartaric acid tolterodine tartrate - Google Patents
Dispersed tablet of tartaric acid tolterodine tartrate Download PDFInfo
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- CN1628646A CN1628646A CN 200410057363 CN200410057363A CN1628646A CN 1628646 A CN1628646 A CN 1628646A CN 200410057363 CN200410057363 CN 200410057363 CN 200410057363 A CN200410057363 A CN 200410057363A CN 1628646 A CN1628646 A CN 1628646A
- Authority
- CN
- China
- Prior art keywords
- tolterodine tartrate
- tablet
- tolterodine
- disintegrating agent
- tablet formulation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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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 5
- 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 39
- 238000002360 preparation method Methods 0.000 claims abstract description 16
- 239000000654 additive Substances 0.000 claims abstract 3
- 230000000996 additive effect Effects 0.000 claims abstract 3
- 239000007919 dispersible tablet Substances 0.000 claims description 20
- 239000007916 tablet composition Substances 0.000 claims description 17
- 229920002472 Starch Polymers 0.000 claims description 9
- 239000008107 starch Substances 0.000 claims description 9
- 235000019698 starch Nutrition 0.000 claims description 9
- 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 6
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 6
- 239000011734 sodium Substances 0.000 claims description 6
- 229910052708 sodium Inorganic materials 0.000 claims description 6
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 5
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 5
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 5
- MYRTYDVEIRVNKP-UHFFFAOYSA-N 1,2-Divinylbenzene Chemical compound C=CC1=CC=CC=C1C=C MYRTYDVEIRVNKP-UHFFFAOYSA-N 0.000 claims description 4
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 4
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 4
- 229940084030 carboxymethylcellulose calcium Drugs 0.000 claims description 4
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 4
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 4
- 229960004045 tolterodine Drugs 0.000 claims description 4
- OOGJQPCLVADCPB-HXUWFJFHSA-N tolterodine Chemical compound C1([C@@H](CCN(C(C)C)C(C)C)C=2C(=CC=C(C)C=2)O)=CC=CC=C1 OOGJQPCLVADCPB-HXUWFJFHSA-N 0.000 claims description 4
- BDIAUFOIMFAIPU-UHFFFAOYSA-N valepotriate Natural products CC(C)CC(=O)OC1C=C(C(=COC2OC(=O)CC(C)C)COC(C)=O)C2C11CO1 BDIAUFOIMFAIPU-UHFFFAOYSA-N 0.000 claims description 4
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims description 2
- 229920001634 Copolyester Polymers 0.000 claims description 2
- 229920001503 Glucan Polymers 0.000 claims description 2
- 229920002907 Guar gum Polymers 0.000 claims description 2
- -1 IRP-88 Polymers 0.000 claims description 2
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 claims description 2
- 229920000881 Modified starch Polymers 0.000 claims description 2
- 235000010980 cellulose Nutrition 0.000 claims description 2
- 229920002678 cellulose Polymers 0.000 claims description 2
- 239000001913 cellulose Substances 0.000 claims description 2
- 238000004132 cross linking Methods 0.000 claims description 2
- 239000003292 glue Substances 0.000 claims description 2
- 239000000665 guar gum Substances 0.000 claims description 2
- 235000010417 guar gum Nutrition 0.000 claims description 2
- 229960002154 guar gum Drugs 0.000 claims description 2
- 150000001261 hydroxy acids Chemical class 0.000 claims description 2
- 239000001341 hydroxy propyl starch Substances 0.000 claims description 2
- 235000013828 hydroxypropyl starch Nutrition 0.000 claims description 2
- TWNIBLMWSKIRAT-VFUOTHLCSA-N levoglucosan Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@H]2CO[C@@H]1O2 TWNIBLMWSKIRAT-VFUOTHLCSA-N 0.000 claims description 2
- 235000010413 sodium alginate Nutrition 0.000 claims description 2
- 239000000661 sodium alginate Substances 0.000 claims description 2
- 229940005550 sodium alginate Drugs 0.000 claims description 2
- FEWJPZIEWOKRBE-XIXRPRMCSA-N Mesotartaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-XIXRPRMCSA-N 0.000 claims 3
- 239000000126 substance Substances 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 21
- 230000000694 effects Effects 0.000 abstract description 11
- 206010046543 Urinary incontinence Diseases 0.000 abstract description 8
- 230000027939 micturition Effects 0.000 abstract description 8
- 230000008901 benefit Effects 0.000 abstract description 5
- 238000010521 absorption reaction Methods 0.000 abstract description 4
- 239000006185 dispersion Substances 0.000 abstract 2
- 230000002411 adverse Effects 0.000 abstract 1
- 239000000470 constituent Substances 0.000 abstract 1
- 238000004090 dissolution Methods 0.000 description 21
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 16
- 238000005516 engineering process Methods 0.000 description 13
- 239000000945 filler Substances 0.000 description 12
- 238000000338 in vitro Methods 0.000 description 12
- 239000000314 lubricant Substances 0.000 description 11
- 239000011230 binding agent Substances 0.000 description 10
- 230000001186 cumulative effect Effects 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 238000009825 accumulation Methods 0.000 description 8
- 235000019359 magnesium stearate Nutrition 0.000 description 8
- 229940079593 drug Drugs 0.000 description 7
- 238000011282 treatment Methods 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N EtOH Substances CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 208000005946 Xerostomia Diseases 0.000 description 6
- 206010013781 dry mouth Diseases 0.000 description 6
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 229940016286 microcrystalline cellulose Drugs 0.000 description 5
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 5
- 239000008108 microcrystalline cellulose Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000008187 granular material Substances 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 230000002354 daily effect Effects 0.000 description 3
- 102000005962 receptors Human genes 0.000 description 3
- 108020003175 receptors Proteins 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 2
- 229940121948 Muscarinic receptor antagonist Drugs 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 230000003203 everyday effect Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000003149 muscarinic antagonist Substances 0.000 description 2
- 210000003681 parotid gland Anatomy 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- RKUNBYITZUJHSG-FXUDXRNXSA-N (S)-atropine Chemical compound C1([C@@H](CO)C(=O)O[C@H]2C[C@H]3CC[C@@H](C2)N3C)=CC=CC=C1 RKUNBYITZUJHSG-FXUDXRNXSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 102000004506 Blood Proteins Human genes 0.000 description 1
- 108010017384 Blood Proteins Proteins 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 208000019505 Deglutition disease Diseases 0.000 description 1
- XIQVNETUBQGFHX-UHFFFAOYSA-N Ditropan Chemical compound C=1C=CC=CC=1C(O)(C(=O)OCC#CCN(CC)CC)C1CCCCC1 XIQVNETUBQGFHX-UHFFFAOYSA-N 0.000 description 1
- RKUNBYITZUJHSG-UHFFFAOYSA-N Hyosciamin-hydrochlorid Natural products CN1C(C2)CCC1CC2OC(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-UHFFFAOYSA-N 0.000 description 1
- 206010020853 Hypertonic bladder Diseases 0.000 description 1
- DHUZAAUGHUHIDS-ONEGZZNKSA-N Isomyristicin Chemical compound COC1=CC(\C=C\C)=CC2=C1OCO2 DHUZAAUGHUHIDS-ONEGZZNKSA-N 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
- 229930195725 Mannitol Natural products 0.000 description 1
- 229940123445 Tricyclic antidepressant Drugs 0.000 description 1
- 208000000921 Urge Urinary Incontinence Diseases 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 1
- 230000001022 anti-muscarinic effect Effects 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
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- 230000008602 contraction Effects 0.000 description 1
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- 201000006549 dyspepsia Diseases 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 229960000855 flavoxate Drugs 0.000 description 1
- SPIUTQOUKAMGCX-UHFFFAOYSA-N flavoxate Chemical compound C1=CC=C2C(=O)C(C)=C(C=3C=CC=CC=3)OC2=C1C(=O)OCCN1CCCCC1 SPIUTQOUKAMGCX-UHFFFAOYSA-N 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229960003210 hyoscyamine Drugs 0.000 description 1
- 229930005342 hyoscyamine Natural products 0.000 description 1
- 229960004801 imipramine Drugs 0.000 description 1
- BCGWQEUPMDMJNV-UHFFFAOYSA-N imipramine Chemical compound C1CC2=CC=CC=C2N(CCCN(C)C)C2=CC=CC=C21 BCGWQEUPMDMJNV-UHFFFAOYSA-N 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
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- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 229960005434 oxybutynin Drugs 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 229960005439 propantheline bromide Drugs 0.000 description 1
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- 229940105346 tolterodine tartrate 2 mg Drugs 0.000 description 1
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- 206010046494 urge incontinence Diseases 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 invention discloses a tolterodine tartrate dispersed tablet, which comprises tolterodine tartrate as main constituent as well as disintegrating agent, and auxiliary additive, the disintegrating agent is of dispersion tablet type commonly used, while the auxiliary addition agent is the commonly used dispersion tablet type addition agent. The dosage has the advantages of easy administration for the elderly and children, stabilized preparation, quick absorption, high biological availability, and less adverse effect. The dosage can be used as a medicament for treating frequent 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 toleration is obviously good than the latter.Because Tolterodine tartrate has good toleration, has improved patient's compliance, 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 1～4mg, 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 the 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, (A～H), its dissolution in vitro experimental technique is as follows for prescription: measure according to high performance liquid chromatography (two appendix VD of Chinese Pharmacopoeia version in 2000) for the mensuration Tolterodine tartrate dispersible tablet of Tolterodine tartrate dispersible tablet dissolution in vitro.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 XC of Chinese Pharmacopoeia version in 2000 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 description of drawings 1～6 for details.
Table 1: the cumulative in vitro dissolution of prescription A
| Time (min) | ????5 | ????10 | ????15 | ????20 | ????25 | ????30 |
| Accumulation dissolution (%) | ????62 | ????73 | ????84 | ????95 | ????97 | ????99 |
| Disperse the time limit | 2.7min disintegrate, and can be all by No. 2 sieves | |||||
Table 2: the cumulative in vitro dissolution of prescription B
| Time (min) | ????5 | ????10 | ????15 | ????20 | ????25 | ????30 |
| Accumulation dissolution (%) | ????66 | ????74 | ????85 | ????95 | ????99 | ????99 |
| Disperse the time limit | 2.1min disintegrate, and can be all by No. 2 sieves | |||||
Table 3: the cumulative in vitro dissolution of prescription C
Table 3: the cumulative in vitro dissolution of prescription C
| Time (min) | 5 | ?10 | ?15 | ?20 | ?25 | ?30 |
| Accumulation dissolution (%) | 71 | ?85 | ?94 | ?97 | ?97 | ?97 |
| Disperse the time limit | 1.6min disintegrate, and can be all by No. 2 sieves | |||||
Table 4: the cumulative in vitro dissolution of prescription D
| Time (min) | ????5 | ????10 | ????15 | ????20 | ????25 | ????30 |
| Accumulation dissolution (%) | ????78 | ????89 | ????95 | ????95 | ????97 | ????97 |
| Disperse the time limit | 1.1min disintegrate, and can be all by No. 2 sieves | |||||
Table 5: the cumulative in vitro dissolution of prescription E
| Time (min) | ????5 | ????10 | ????15 | ????20 | ????25 | ????30 |
| Accumulation dissolution (%) | ????83 | ????91 | ????95 | ????99 | ????99 | ????99 |
| Disperse the time limit | 0.8min disintegrate, and can be all by No. 2 sieves | |||||
Table 6: the cumulative in vitro dissolution of prescription F
| Time (min) | ????5 | ????10 | ????15 | ????20 | ????25 | ????30 |
| Accumulation dissolution (%) | ????85 | ????93 | ????97 | ????97 | ????99 | ????99 |
| Disperse the time limit | 0.6min disintegrate, and can be all by No. 2 sieves | |||||
Table 7: the cumulative in vitro dissolution of prescription G
| Time (min) | 5 | ?10 | ?15 | ?20 | ?25 | ????30 |
| Accumulation dissolution (%) | 89 | ?94 | ?95 | ?97 | ?97 | ????97 |
| Disperse the time limit | 0.4min disintegrate, and can be all by No. 2 sieves | |||||
Table 8: the cumulative in vitro dissolution of prescription H
| Time (min) | ????5 | ????10 | ????15 | ????20 | ????25 | ????30 |
| Accumulation dissolution (%) | ????91 | ????95 | ????99 | ????99 | ????99 | ????99 |
| Disperse the time limit | 0.2min disintegrate, and can be all by No. 2 sieves | |||||
Claims (7)
1, a kind of 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:
(2) disintegrating agent
(3) pharmaceutically useful auxiliary additive is a preparation tablet formulation pharmaceutically acceptable tablet formulation additive commonly used.
2, the described Tolterodine tartrate tablet formulation of claim 1 is characterized in that described disintegrating agent is one or more 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.
3, the described tablet formulation of claim 1 is characterized in that the amount of every described Tolterodine tartrate dispersible tablet mesotartaric acid tolterodine is optimized for 0.1～20mg.
4, the described tablet formulation of claim 1 is characterized in that the amount of every described Tolterodine tartrate dispersible tablet mesotartaric acid tolterodine more is optimized for 1～8mg.
5, the described tablet formulation of claim 1 is characterized in that the amount optimum of every described Tolterodine tartrate dispersible tablet mesotartaric acid tolterodine turns to 2mg.
6, claim 1,2 described tablet formulations, the content that it is characterized in that every described disintegrating agent is 1～80%.
7, claim 1,2 described tablet formulations, the content that it is characterized in that every described disintegrating agent is 10～30%.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100573635A CN100382794C (en) | 2004-08-30 | 2004-08-30 | Dispersed tablet of tartaric acid tolterodine tartrate |
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| CNB2004100573635A CN100382794C (en) | 2004-08-30 | 2004-08-30 | Dispersed tablet of tartaric acid tolterodine tartrate |
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| CN1628646A true CN1628646A (en) | 2005-06-22 |
| CN100382794C CN100382794C (en) | 2008-04-23 |
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Cited By (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 |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU728395B2 (en) * | 1996-07-19 | 2001-01-11 | Gunnar Aberg | S(-)-tolterodine in the treatment of urinary and gastrointestinal disorders |
| EE05191B1 (en) * | 1999-11-11 | 2009-08-17 | Pharmacia Ab | A pharmaceutical composition comprising tolterodine and its use |
| CN1558756A (en) * | 2001-09-27 | 2004-12-29 | �ź㴫 | Pharmaceutical compositions for the treatment of urinary disorders |
-
2004
- 2004-08-30 CN CNB2004100573635A patent/CN100382794C/en not_active Expired - Fee Related
Cited By (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 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN100382794C (en) | 2008-04-23 |
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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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