CN103142465B - Tolterodine film-forming hydrogel preparation and preparation method thereof - Google Patents
Tolterodine film-forming hydrogel preparation and preparation method thereof Download PDFInfo
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- CN103142465B CN103142465B CN201310086030.4A CN201310086030A CN103142465B CN 103142465 B CN103142465 B CN 103142465B CN 201310086030 A CN201310086030 A CN 201310086030A CN 103142465 B CN103142465 B CN 103142465B
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Abstract
The invention discloses a tolterodine film-forming hydrogel preparation. A preparation method comprises the following steps of: directly adopting tolterodine tartrate to prepare the tolterodine film formation hydrogel preparation which utilizes carbomer 980 and hydroxypropyl cellulose as a mixed gel, water and ethanol as a solvent, methyl cellulose as a film-forming agent, polysorbate 80 as a film mechanical strength modifier and triethanolamine as a pH modifier and a drug transforming agent. The preparation has the drug-loading rate of 4-10%, the gel is transparent, the drug is uniformly dispersed, a transparent drug film is formed after the preparation is applied, and the application volume of the preparation is less than 0.5ml. The preparation can be stably released for 24 hours after being applied, and the bioavailability of the preparation is more than 20%. The prepared gel is smooth, crystal and fine, does not generate a foreign body sensation to skin after being applied, is slow in drug sustainable release, has a good percutaneous absorption effect and is convenient to use, and the compliance of patients is improved.
Description
technical field:
The present invention is the improvement to tolterodine pharmaceutical dosage form, is further open a kind of tolterodine film forming aqueogel, and the present invention also provides the preparation method of described preparation, belongs to medical science pharmaceutical technology field.
background technology:
Tolterodine belongs to 3,3 diphenylprop amine muscarinic receptor antagonists, and oral body inner blood Chinese medicine fluctuation of concentration is large, causes drug effect low, and side effect increases, for example xerostomia, constipation, dyspepsia, headache, dizzy, dry, urine retention.Its unabsorbed part will produce the front side effect of system or interaction (EP1077912), and first pass effect of hepar also causes drug effect to reduce, and side effect increases.Although can pass through the administration of normal injection mode, for urine incontinence long-term treatment, injection system once a day or repeatedly will increase the painful and uncomfortable of patient.
The transdermal delivery system of the present invention exploitation is film forming aqueogel, and the medicine that is generally applicable to prepare hydrogel need possess suitable Determination of oil-water partition coefficient, make in gel solvent dissolubility higher, and percutaneous abilities is good.If drug solubility does not reach preparation requirement, in document, reporting maximum is to prepare medicine microemulsion gel, but there is no listing preparation, main cause is micro emulsion gel in long-term preservation process, and emulsion droplet easily merges, and breaks etc., cause medicine to be separated out, thermodynamic stability is bad.Mesotartaric acid tolterodine of the present invention equal slightly soluble in water and ethanol, is not suitable for preparing its high drug load hydrogel taking these two kinds of materials as solvent, and Tolterodine tartrate transdermal capability a little less than.Improve drug transdermal ability if want, need first Tolterodine tartrate to be converted into free alkali tolterodine.Free alkali tolterodine physical behavior is thickness semisolid, the more difficult control of quality in commercial production, in addition, if employing inorganic base, obtain free alkali tolterodine as NaOH transforms Tolterodine tartrate, residual soluble tartar hydrochlorate destructible carbomer gel structure in product, causes being difficult to prepare high drug load gel, and atomic molten in free alkali tolterodine water in hydrogel, cause gel water content to be difficult for too high.
summary of the invention:
The invention provides a kind of tolterodine film forming aqueogel, percutaneous dosing is smeared in external, solved free alkali tolterodine quality control difficulty in commercial production, internal metabolism individual variation is large, and Tolterodine tartrate is difficult for preparing hydrogel and gel preparation and smears and easily the problems such as taken away by medicated clothing afterwards.
The present invention can effectively improve the bioavailability of medicine aqueogel.
The present invention also provides the preparation method of tolterodine film forming hydrogel adhesive, comprises weighing, application of sample, stirring three steps, simple to operate, is applicable to suitability for industrialized production.
a kind of tolterodine film-forming gel preparation provided by the invention, mainly comprises following component (quality %):
4～10% Tolterodine tartrates, 0.15～0.225% gel, 1～2% film former, the pH adjusting agent of 5%-10%, 0%～2% film properties regulator, 32% ethanol and distilled water are to total amount 100%;
Described gel is Carbopol and hydroxypropyl cellulose mixture, and mixed proportion is 2:1;
Described one-tenth membrane matrix is hydroxypropyl methylcellulose;
Described pH adjusting agent is triethanolamine;
Described film properties regulator is Tween 80.
the preferred tolterodine film forming of the present invention aqueogel, comprises following component (quality %):
0.8767% Tolterodine tartrate, 0.1% carbomer, 0.05% hydroxypropyl cellulose, 1.25%-1.75% hydroxypropyl methylcellulose, 0.05%-1.5% Tween 80, the triethanolamine of 6%-9%, the distilled water of 32% ethanol and surplus is to total amount 100%.
the preparation method of tolterodine film forming aqueogel of the present invention, comprises the following steps:
Triethanolamine, ethanol, Tween 80 are joined in the container containing Tolterodine tartrate, Carbopol, hydroxypropyl cellulose and hydroxypropyl methylcellulose, after stirring, add surplus distilled water and mend to total amount 100%, continue to be stirred to homogeneous transparent.
the invention has the beneficial effects as follows:
By screening gel and film former adding proportion time, control triethanolamine addition, successfully overcome above technology barrier, triethanolamine in prescription except the carbomer pH adjusting agent as conventional, another very important function is directly to react with Tolterodine tartrate to generate free alkali tolterodine, the tartrate generating can not destroy gel structure that carbomer becomes, and triethanolamine can increase substantially tolterodine dissolubility, make medicine, gel and the film former compatibility are good, 6% drug loading gel at water content up to 50% time, in preservation process, tolterodine also can not be separated out, overcome gel preparation common be prone to problem that drug crystallization is separated out, soon replacing with regard to delisting sieve as firm listing can spit of fland transdermal absorption formulation.
The present invention, by adding Klucel EF, has effectively improved gel physical behavior, makes become gel quality finer and smoother, smears more comfortablely, has improved the bioavailability of gel simultaneously.Interpolation hydroxypropyl methylcellulose makes to prepare aqueogel and possesses film property, and drug release is milder and use more convenient.Tween 80 is conventional wetting agent, surfactant, and in the present invention, the Tween 80 Main Function of few additive is the character of regulating drug film, thereby affects drug transdermal behavior, and medicine in 24h is discharged closer to zero level.In order further to obtain well behaved Tolterodine gel preparation, the present invention is on experiment of single factor basis, adopt response surface method to be optimized the addition of key factor in pharmaceutical formulation, finally obtained the high drug load Tolterodine tartrate film forming aqueogel of steady sustained release in 24h.
The present invention and US6517864 have reported 24 hours transdermal dosage forms comparison of tolterodine, main advantage is: directly adopt the Tolterodine tartrate preparation can film forming hydrogel, avoided preparing the quality Control that free alkali tolterodine exists, technique is simple, and cost is low; Medicine is carried out to skin external administration with the form of hydrogel, use more conveniently and comfortable than patch, and agents area is non-air-tight state, also little to the stimulation of skin; Different from most of hydrogels is to smear rear matcoveredn to exist, and preparation can not taken away by medicated clothing etc., can not cause that drug effect reduces, and avoids polluting; The most important thing is in the situation that drug loading is higher, be no matter preparation itself or use after in institute's film forming, medicine can crystallization, good stability.The gel of preparation is smooth, sparkling and crystal-clear, fine and smooth, and with the sense of rear skin foreign, medicine is lasting slowly to be discharged, and percutaneous good absorbing effect is easy to use, improves patient's compliance.
brief description of the drawings:
Fig. 1 is that embodiment 1 prepares gel transdermal test in vitro preparation-time graph;
Fig. 2 is that embodiment 2 prepares gel transdermal test in vitro preparation-time graph;
Fig. 3 is that embodiment 3 prepares gel transdermal test in vitro preparation-time graph;
Fig. 4 is that embodiment 4 prepares gel transdermal test in vitro preparation-time graph;
Fig. 5 is that embodiment 5 prepares gel transdermal test in vitro preparation-time graph;
Fig. 6 is that embodiment 6 prepares gel transdermal test in vitro preparation-time graph;
Fig. 7 is that embodiment 7 prepares gel transdermal test in vitro preparation-time graph;
Fig. 8 is that embodiment 8 prepares gel transdermal test in vitro preparation-time graph;
Fig. 9 is that embodiment 9 prepares gel transdermal test in vitro preparation-time graph;
Figure 10 is that embodiment 10 prepares gel transdermal test in vitro preparation-time graph;
Figure 11 is that embodiment 11 prepares gel transdermal test in vitro preparation-time graph;
Figure 12 is that embodiment 12 prepares gel transdermal test in vitro preparation-time graph;
Figure 13 is 5 batches of gel transdermal test in vitro preparation-time graphs prepared by embodiment 13;
Figure 14 is that embodiment 14 prepares gel transdermal test in vitro preparation-time graph;
Figure 15 is film forming situation on gel microscope slide in effect experimental example 1;
Figure 16 is the space three-dimensional figure of embodiment 1-13 response surface analysis;
Figure 17 is to rabbit vein injection tolterodine solution and smears embodiment 14 and prepare the blood drug level-time graph after gel.
Detailed description of the invention
Specific embodiment of the invention method, illustrated, but protection scope of the present invention is not limited to this by following embodiment.
embodiment 1
By following formula preparation gel (by 10g):
Tolterodine tartrate 0.5844g, Carbopol 0.1g, hydroxypropyl cellulose (HPC) 0.05g, triethanolamine 0.5997g, hydroxypropyl methylcellulose (HPMC) 0.1g, ethanol 4ml, tween 0.1g, surplus is distilled water.
After Tolterodine tartrate, Carbopol, HPC, HPMC are weighed, add in beaker, add ethanol, triethanolamine, Tween 80, stir, mend and add water to 10g, be stirred to gel homogeneous transparent, pack into and in cillin bottle, seal room temperature preservation.Transdermal test in vitro preparation-time graph is shown in Fig. 1.
embodiment 2
By following formula preparation gel (by 10g):
Tolterodine tartrate 0.5844g, Carbopol 0.1g, hydroxypropyl cellulose (HPC) 0.05g, triethanolamine 0.5997g, hydroxypropyl methylcellulose (HPMC) 0.15g, ethanol 3.2g, tween 0.1g, surplus is distilled water.
After Tolterodine tartrate, Carbopol, HPC, HPMC are weighed, add in beaker, add ethanol, triethanolamine, Tween 80, stir, mend and add water to 10g, be stirred to gel homogeneous transparent, pack into and in cillin bottle, seal room temperature preservation.Transdermal test in vitro preparation-time graph is shown in Fig. 2.
embodiment 3tolterodine tartrate gel preparation
By following formula preparation gel (by 10g):
Tolterodine tartrate 0.8767g, Carbopol 0.1g, hydroxypropyl cellulose (HPC) 0.05g, triethanolamine 0.783g, hydroxypropyl methylcellulose (HPMC) 0.1g, ethanol 3.2g, tween 0.1g, surplus is distilled water.
After Tolterodine tartrate, Carbopol, HPC, HPMC are weighed, add in beaker, add ethanol, triethanolamine, Tween 80, stir, mend and add water to 10g, be stirred to gel homogeneous transparent, pack into and in cillin bottle, seal room temperature preservation.Transdermal test in vitro preparation-time graph is shown in Fig. 3.
embodiment 4
By following formula preparation gel (by 10g):
Tolterodine tartrate 0.8767g, Carbopol 0.1g, hydroxypropyl cellulose (HPC) 0.05g, triethanolamine 0.783g, hydroxypropyl methylcellulose (HPMC) 0.2g, ethanol 3.2g, tween 0.1g, surplus is distilled water.
After Tolterodine tartrate, Carbopol, HPC, HPMC are weighed, add in beaker, add ethanol, triethanolamine, Tween 80, stir, mend and add water to 10g, be stirred to gel homogeneous transparent, pack into and in cillin bottle, seal room temperature preservation.Transdermal test in vitro preparation-time graph is shown in Fig. 4.
embodiment 5
By following formula preparation gel (by 10g):
Tolterodine tartrate 0.7305g, Carbopol 0.1g, hydroxypropyl cellulose (HPC) 0.05g, triethanolamine 0.6913g, hydroxypropyl methylcellulose (HPMC) 0.1g, ethanol 3.2g, surplus is distilled water.
After Tolterodine tartrate, Carbopol, HPC, HPMC are weighed, add in beaker, add ethanol, triethanolamine, stir, mend and add water to 10g, be stirred to gel homogeneous transparent, pack into and in cillin bottle, seal room temperature preservation.Transdermal test in vitro preparation-time graph is shown in Fig. 5.
embodiment 6
By following formula preparation gel (by 10g):
Tolterodine tartrate 0.7305g, Carbopol 0.1g, hydroxypropyl cellulose (HPC) 0.05g, triethanolamine 0.6913g, hydroxypropyl methylcellulose (HPMC) 0.1g, ethanol 3.2g, tween 0.2g, surplus is distilled water.
After Tolterodine tartrate, Carbopol, HPC, HPMC are weighed, add in beaker, add ethanol, triethanolamine, Tween 80, stir, mend and add water to 10g, be stirred to gel homogeneous transparent, pack into and in cillin bottle, seal room temperature preservation.Transdermal test in vitro preparation-time graph is shown in Fig. 6.
embodiment 7
By following formula preparation gel (by 10g):
Tolterodine tartrate 0.7305g, Carbopol 0.1g, hydroxypropyl cellulose (HPC) 0.05g, triethanolamine 0.6913g, hydroxypropyl methylcellulose (HPMC) 0.15g, ethanol 3.2g, surplus is distilled water.
After Tolterodine tartrate, Carbopol, HPC, HPMC are weighed, add in beaker, add ethanol, triethanolamine, stir, mend and add water to 10g, be stirred to gel homogeneous transparent, pack into and in cillin bottle, seal room temperature preservation.Transdermal test in vitro preparation-time graph is shown in Fig. 7.
embodiment 8
By following formula preparation gel (by 10g):
Tolterodine tartrate 0.7305g, Carbopol 0.1g, hydroxypropyl cellulose (HPC) 0.05g, triethanolamine 0.6913g, hydroxypropyl methylcellulose (HPMC) 0.2g, ethanol 3.2g, tween 0.2g, surplus is distilled water.
Tolterodine tartrate, Carbopol, HPC, HPMC are added in beaker after weighing, add ethanol, triethanolamine, Tween 80, stir, benefit adds water to 10g, be stirred to gel homogeneous transparent, pack in cillin bottle and seal room temperature preservation, transdermal test in vitro preparation-time graph is shown in Fig. 8.
embodiment 9
By following formula preparation gel (by 10g):
Tolterodine tartrate 0.5844g, Carbopol 0.1g, hydroxypropyl cellulose (HPC) 0.05g, triethanolamine 0.5997g, hydroxypropyl methylcellulose (HPMC) 0.15g, ethanol 3.2g, surplus is distilled water.
Tolterodine tartrate, Carbopol, HPC, HPMC are added in beaker after weighing, add ethanol, triethanolamine, stir, benefit adds water to 10g, be stirred to gel homogeneous transparent, pack in cillin bottle and seal room temperature preservation, transdermal test in vitro preparation-time graph is shown in Fig. 9.
embodiment 10
By following formula preparation gel (by 10g):
Tolterodine tartrate 0.8767g, Carbopol 0.1g, hydroxypropyl cellulose (HPC) 0.05g, triethanolamine 0.783g, hydroxypropyl methylcellulose (HPMC) 0.15g, ethanol 3.2g, surplus is distilled water.
Tolterodine tartrate, Carbopol, HPC, HPMC are added in beaker after weighing, add ethanol, triethanolamine, stir, benefit adds water to 10g, be stirred to gel homogeneous transparent, pack in cillin bottle and seal room temperature preservation, transdermal test in vitro preparation-time graph is shown in Figure 10.
embodiment 11
By following formula preparation gel (by 10g):
Tolterodine tartrate 0.5844g, Carbopol 0.1g, hydroxypropyl cellulose (HPC) 0.05g, triethanolamine 0.5997g, hydroxypropyl methylcellulose (HPMC) 0.15g, ethanol 3.2g, tween 0.2g, surplus is distilled water.
Tolterodine tartrate, Carbopol, HPC, HPMC are added in beaker after weighing, add ethanol, triethanolamine, Tween 80, stir, benefit adds water to 10g, be stirred to gel homogeneous transparent, pack in cillin bottle and seal room temperature preservation, transdermal test in vitro preparation-time graph is shown in Figure 11.
embodiment 12
By following formula preparation gel (by 10g):
Tolterodine tartrate 0.8767g, Carbopol 0.1g, hydroxypropyl cellulose (HPC) 0.05g, triethanolamine 0.783g, hydroxypropyl methylcellulose (HPMC) 0.15g, ethanol 3.2g, tween 0.2g, surplus is distilled water.
Tolterodine tartrate, Carbopol, HPC, HPMC are added in beaker after weighing, add ethanol, triethanolamine, Tween 80, stir, benefit adds water to 10g, be stirred to gel homogeneous transparent, pack in cillin bottle and seal room temperature preservation, transdermal test in vitro preparation-time graph is shown in Figure 12.
embodiment 13
By following formula preparation gel (by 10g):
Tolterodine tartrate 0.7305g, Carbopol 0.1g, hydroxypropyl cellulose (HPC) 0.05g, triethanolamine 0.6913g, hydroxypropyl methylcellulose (HPMC) 0.15g, ethanol 3.2g, tween 0.1g, surplus is distilled water.
Tolterodine tartrate, Carbopol, HPC, HPMC are added in beaker after weighing, add ethanol, triethanolamine, Tween 80, stir, benefit adds water to 10g, be stirred to gel homogeneous transparent, pack in cillin bottle and seal room temperature preservation, transdermal test in vitro preparation-time graph is shown in Figure 13.
embodiment 14
By following formula preparation gel (by 10g):
Tolterodine tartrate 0.8767g, Carbopol 0.1g, hydroxypropyl cellulose (HPC) 0.05g, triethanolamine 0.783g, hydroxypropyl methylcellulose (HPMC) 0.131g, ethanol 3.2g, tween 0.133g, surplus is distilled water.
Tolterodine tartrate, Carbopol, HPC, HPMC are added in beaker after weighing, add ethanol, triethanolamine, Tween 80, stir, benefit adds water to 10g, be stirred to gel homogeneous transparent, pack in cillin bottle and seal room temperature preservation, transdermal test in vitro preparation-time graph is shown in Figure 14.
effect experimental example 1
Investigate embodiment 13 medicines at preparation and physical state in using rear institute film forming
Get gel in 0.2g embodiment 13, evenly spread upon on microscope slide, the about 2cm of area
2, at particular point in time Taking Pictures recording.The results are shown in Figure 15: result shows, hydroxypropyl cellulose can make gel have film property, reduces the foreign body sensation after smearing, and colorless transparent gel is after smearing, in 1 minute, ethanol volatilizees rapidly, the medicine precipitate that is white in color in institute's film forming, separates out situation relevant to thickness, and in 3 minutes, institute's film formation surface has possessed certain mechanical strength, do not stick medicated clothing etc., in 30 minutes afterwards, along with the evaporation of moisture, medicine solves homogeneously in film again.
effect experimental example 2
The outer transdermal experiment of gelinite
Use Na
2s sloughs healthy mice abdominal part Mus hair, cleans up, and disconnected neck is put to death, and cuts at once its skin of abdomen, removes subcutaneus adipose tissue and mucous tissue with blade, notes not destroying horny layer, cleans with normal saline, puts in refrigerator and saves backup.
Prepare gel according to embodiment 1～13.From refrigerator, take out Corium Mus, return to room temperature, repeatedly rinse Corium Mus with normal saline, then dry gently with filter paper.Use Franz diffusion cell, skin is fixed between supply chamber and receiving chamber, make stratum corneum side to supply chamber, the two effective contacts area in Room are 0.636cm
2.Precision takes 0.01g gel, put in supply chamber and smoothen, and with skin close contact.In receiving chamber, add phosphate buffer (PBS) 5ml(pH 7.4,10mmol/L), bath temperature is (32 ± 0.5) DEG C, constant speed 200r/min, refill immediately 5ml fresh medium respectively at 1h, 2h, 4h, 6h, 8h, 10h, 12h and 24h timing sampling 5ml(), 0.45 μ m filtering with microporous membrane, HPLC measures receiving liquid Chinese medicine concentration.Every batch of gel does 6 groups of parallel laboratory tests.
HPLC condition is: XDB C18 post 5 μ m, and 4.5mm × 250mm, 40 DEG C of column temperatures, detect wavelength 283nm, and mobile phase is 10mmol/L acetate buffer solution (pH 3.0)-methanol (35:65), flow velocity 1ml/min.
13 batches of gels are as follows with optimization prescription embodiment 14 transdermal release results, wherein J
ssfor stable state drug transdermal speed, Q
24hbe 24 hours drug transdermal amounts:
Result shows, in 13 batches of gels, embodiment 13 repeats 5 times, so as response surface analysis, gel transdermal speed difference, affected by drug loading, HPMC, Tween 80 larger, see Figure 16 with regard to 24 hours preparation analysis results of its response value, wherein, prescription embodiment 14 is optimized: drug loading 6%, HPMC content 1.31%, Tween 80 content 1.33%.
effect experimental example 3
Gel medicine is for experiment
Get healthy mature male rabbit, weight is 1.5～2.5kg, is divided into intravenous injection (i.v.) group and gel group, every group of 3 rabbit.Test the previous day, intramuscular injection 30mg/kg pentobarbital sodium anesthesia gel group rabbit, then removes back wool with shears, and skin can not have breakage, and (size is 4 × 4cm to marking pen labelling for defeathering position
2), fasting 12h.When experiment, gel prepared by embodiment 14 spreads upon defeathering position, notes smearing evenly, and administration 3min relief animal is freely movable.Simultaneously to another group rabbit i.v. tolterodine solution.In experimentation, rabbit is freely intake.
After administration, respectively at 0,15,30min, 1,2,4,6,8,12,24,36 h auricular veins are got blood, collect 1ml blood, put containing in the EP pipe of 20 μ l heparin, and the centrifugal 10min separated plasma of 13,000rpm, to be measured in-20 ° of C Refrigerator stores.
Get 100 μ l blood plasma, add respectively 100 μ l inner mark solutions, 100 μ l acetonitrile-waters (80:20, v/v), solution adds 3 ml to extract reagent (ether: dichloromethane=3:2, v/v), eddy current mixing 30s, vibration 10min, centrifugal 5min(3500 rpm), get supernatant nitrogen at 30 DEG C and dry up, residue adds 150 μ l mobile phases and dissolves, and gets 20 μ l and carries out LC/MS/MS analysis.
I.v. tolterodine and smear embodiment 14 and prepare after gel, rabbit medicine is as follows for experimental result:
| ? | T max(h) | C max(nmol/ml) | AUC 0-48h(nmol/ml)) | Absolute bioavailability (%) |
| Tolterodine i.v. | 0.25 | 19.74 | 76.00 | 100% |
| Embodiment 14 | 1 | 5.67 | 39.81 | 52.38% |
Result shows, the made gel of embodiment 14 can steadily slowly discharge, and bioavailability, higher than 50%, has certain clinical use meaning.
After administration, blood drug level-time graph is shown in Figure of description 17.
Claims (1)
1. a tolterodine film-forming gel preparation, it is characterized in that being made up by weight of following raw material:
Tolterodine tartrate 0.8767g, Carbopol 0.1g, hydroxypropyl cellulose 0.05g, triethanolamine 0.783g, hydroxypropyl methylcellulose 0.131g, ethanol 3.2g, tween 0.133g, surplus is distilled water;
Tolterodine tartrate, Carbopol, HPC, HPMC are added in beaker after weighing, add ethanol, triethanolamine, Tween 80, stir, mend and add water to 10g, be stirred to gel homogeneous transparent and get final product.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6517864B1 (en) * | 1998-08-27 | 2003-02-11 | Pharmacia Ab | Transdermally administered tolterodine as anti-muscarinic agent for the treatment of overactive bladder |
| CN101810565A (en) * | 2010-04-26 | 2010-08-25 | 李又欣 | Tolterodine gel preparation and preparation method thereof |
| CN101843579A (en) * | 2010-05-20 | 2010-09-29 | 李又欣 | 5-hydroxymethyl Tolterodine gel preparation and preparation method thereof |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20110001103A (en) * | 2009-06-29 | 2011-01-06 | 에스케이케미칼주식회사 | Tolterodine-containing transdermal administration composition with improved storage stability |
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2013
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6517864B1 (en) * | 1998-08-27 | 2003-02-11 | Pharmacia Ab | Transdermally administered tolterodine as anti-muscarinic agent for the treatment of overactive bladder |
| CN101810565A (en) * | 2010-04-26 | 2010-08-25 | 李又欣 | Tolterodine gel preparation and preparation method thereof |
| CN101843579A (en) * | 2010-05-20 | 2010-09-29 | 李又欣 | 5-hydroxymethyl Tolterodine gel preparation and preparation method thereof |
Non-Patent Citations (2)
| Title |
|---|
| 刘正和 等.酒石酸托特罗定缓释片的研制.《中国生化药物杂志》.2004,第25卷(第4期),230-232页. |
| 酒石酸托特罗定缓释片的研制;刘正和 等;《中国生化药物杂志》;20041231;第25卷(第4期);230-232页 * |
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