CN105687154A - Pharmaceutical composition containing fesoterodine and preparation method thereof - Google Patents
Pharmaceutical composition containing fesoterodine and preparation method thereof Download PDFInfo
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- CN105687154A CN105687154A CN201410706863.0A CN201410706863A CN105687154A CN 105687154 A CN105687154 A CN 105687154A CN 201410706863 A CN201410706863 A CN 201410706863A CN 105687154 A CN105687154 A CN 105687154A
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Abstract
The invention brings forward a pharmaceutical composition containing fesoterodine and a preparation method thereof. The pharmaceutical composition also comprises a stabilizing agent, which is dextrin, maltodextrin, mannitol, propylene glycol and/or cane sugar. The preparation method of the pharmaceutical composition comprises steps of sieving, mixing, wetting, granulating, drying, tabletting and coating. According to the pharmaceutical composition, the problem that fesoterodine is easy to decompose under conditions of high temperature and high humidity is solved, and the problem that a medicinal excipient in an existing pharmaceutical composition containing fesoterodine has side effect on intestines and stomach is also solved.
Description
Technical field
The present invention relates to pharmaceutical composition of a kind of fesoterodine or its pharmaceutically-acceptable salts and preparation method thereof。
Background technology
Fumaric acid fesoterodine, it is referred to alternatively as 2-[(R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-4-(methylol) phenyl isobutyl acid esters difumarate on chemistry, and its structural formula is as follows:
Fumaric acid fesoterodine is used for treating overactive bladder (OAB), the slow releasing tablet that Pfizer develops was in FDA approval listing in 2008, this product treatment overactive bladder, 1 time on the one, can substantially reduce urgency incontinence morbidity and the number of times urinated for 24 hours。
Fumaric acid fesoterodine system muscarinic receptor competitiveness blocker, is quickly extensively hydrolyzed into active metabolite 5-methylol tolterodine by nonspecific esterase after oral, play the anti-muscarine activity of fesoterodine。The effect of muscarinic receptor is to shrink urinary system smooth muscle of bladder and exciting salivary secretion, and fesoterodine is by suppressing the mechanisms play effect of these bladder receptors。
Fumaric acid fesoterodine is white powder, arbitrarily dissolves in water, poor stability, under high temperature and super-humid conditions, a large amount of degraded easily occurs, is mainly hydrolysis and fumaric acid esterification and Oxidation。Therefore, exploitation fumaric acid fesoterodine pharmaceutical composition it may first have to solve its stability problem。Patent CN101466371A discloses a kind of fumaric acid fesoterodine Pharmaceutical composition, specific pharmaceutical excipient is selected to mix employing wet granulation with principal agent, after mixing with other components again, tabletting, slow releasing tablet prepared into by coating, the addition of specific pharmaceutical excipient slow down the degraded of fesoterodine, reach good effect, but selected stabilizer xylitol, not easily decomposed by gastric enzyme and be directly entered intestinal, after excessive, gastrointestinal is had certain stimulation, it is possible to cause abdominal discomfort, flatulence, borborygmus。And due to xylitol in intestinal internal absorption factor less than 20%, it is easy to accumulate at intestinal wall, easily cause osmotic diarrhea。It addition, in preparation process, major part adjuvant has neither part nor lot in granulation but is directly mixed with tabletting, therefore to framework material hypromellose, the particle diameter of diluent lactose and microcrystalline Cellulose and mobility require higher。
Summary of the invention
For solving above-mentioned prior art Problems existing, the present invention proposes a kind of Pharmaceutical composition containing fesoterodine and preparation method thereof, this Pharmaceutical composition not only solves fesoterodine in problem labile under high temperature and super-humid conditions, also solves the Pharmaceutical composition of the existing fesoterodine problem to the intestines and stomach side effect。
The technical scheme is that and be achieved in that:
A kind of Pharmaceutical composition containing fesoterodine, described Pharmaceutical composition also includes stabilizer, and described stabilizer is dextrin, maltodextrin, mannitol, propylene glycol and/or sucrose。
Further, described stabilizer is dextrin, maltodextrin, mannitol or propylene glycol。
Further, described stabilizer is dextrin or maltodextrin。
Further, described stabilizer is 0.10～50:1 with the weight ratio of fesoterodine。
Further, medicinal acceptable filler, binding agent, disintegrating agent, lubricant and/or stomach dissolution type thin film coating material are also included。
Further, described fesoterodine comprises its pharmaceutically acceptable salt, and described salt is two or tricarboxylate, or be partly hydrogenated two or tricarboxylic salt。
Further, the pharmaceutically acceptable salt of described fesoterodine is fumaric acid fesoterodine。
Further, described stabilizer is 5～30:1 with the weight ratio of described fumaric acid fesoterodine。
Further, described fumaric acid fesoterodine, stabilizer, lactose, microcrystalline Cellulose, hypromellose, Glyceryl Behenate weight ratio be 4～8: 20～200: 20～250: 10～100: 50～200:2～20, it is preferred to 4: 100: 65: 25: 100:9。
Further, the Pharmaceutical composition of the present invention can make tablet, capsule or granule；
Preferably, the mode of taking of described Pharmaceutical composition is for swallowing；Preferably, in described Pharmaceutical composition, the weight ratio of the gross weight of fumaric acid fesoterodine and preparation is 1: 50～100。
The preparation method of a kind of Pharmaceutical composition containing fesoterodine, comprises the following steps:
1) with the stabilizer in claim 1, fesoterodine is crossed 40～120 mesh sieves to mix homogeneously, then cross 40～120 mesh sieves with filler, binding agent and disintegrating agent and mix homogeneously；
2) making wetting agent with the aqueous solution of ethanol, said mixture material carries out soft material processed, cross 18～30 mesh sieve wet granulars, wet granular dries to obtain dry granule through 40 DEG C to 60 DEG C；
3) step 2 is taken) dry granule crosses 14～20 mesh sieve granulate, adds lubricant mixing, then tabletting；
4) carry out coating with stomach dissolution type thin film coating material, obtain Pharmaceutical composition。
Further, step 2) described wetting agent be volumetric concentration is the alcoholic solution of 80～100%, step 3) described lubricant is selected from Glyceryl Behenate, Pulvis Talci and/or magnesium stearate。
The concrete preparation method of described Pharmaceutical composition is:
1. take fumaric acid fesoterodine and a certain amount of stabilizer (selected from dextrin, maltodextrin, mannitol, propylene glycol, sucrose one or more), cross 40～100 mesh sieve mix homogeneously；Take other solid preparation molding adjuvant a certain amount of again, such as hypromellose, lactose, microcrystalline Cellulose etc., add wherein, and cross 40 orders to 100 mesh sieve mix homogeneously。
2. being wetting agent with the aqueous solution of ethanol, above-mentioned mixed material carries out soft material processed, cross 18～30 mesh sieve wet granulars, wet granular is dried to moisture less than 4.0% through 40 DEG C～50 DEG C, obtains dry granule, and dry granule moisture level is 0.5%～4%；Wherein ethanol volumetric concentration is 75%～100%, it is preferred to 95% ethanol。
3. dry granule moves to and carries out granulate in pelletizing machine, and granulate order number is 18～30 orders, puts in blender by dry granule, adds lubricant, mixing, is pressed into the tablet containing principal agent fumaric acid fesoterodine 4mg or 8mg according to clinical application demand；Wherein lubricant is preferably one or more in Glyceryl Behenate, Pulvis Talci, magnesium stearate, and consumption is the 0.5% to 5.0% of whole weight of material。
4. coating
4.1 prepare coating solution
Being put by water and at the uniform velocity stir under agitator to swirling occur, be slowly added to coating material along whirlpool outer rim, stirring makes to be uniformly dispersed, and uses, filter through 80 eye mesh screens before using after maintaining stirring 1 hour。
4.2 coatings
Label preheats: put by label in coating pan, regulates suitable rotating speed, drum hot blast (controlling about about 60 DEG C), makes label temperature control 35～45 DEG C；Regulating the pressure, inlet temperature, coating solution flow velocity and the pot rotating speed that are suitable for, label temperature controls 35～45 DEG C；According to precoating situation, the coating parameter remaining certain carries out coating, observes coating situation (label temperature, prevent bonding die, flower sheet) at any time and and does corresponding parameter adjustment, terminate to coating in coating process, final controls coating weight gain 2%～4%。
Beneficial effects of the present invention:
1) present inventor has performed lot of experiments to improve the stability of fumaric acid fesoterodine, found that: except the excipient listed by patent CN101466371A, after still having some to mix by a certain percentage with principal agent fumaric acid fesoterodine containing polyhydroxy structure pharmaceutical excipient, again with other solid preparation molding excipient, such as framework material hypromellose, diluent etc. mix, adopt the wet granulation being different from above-mentioned patent, obtained fumaric acid fesoterodine slow releasing tablet has good stability, can solve the problem that the technical problem that principal agent fumaric acid fesoterodine is degradable, also solve the pharmaceutical excipient in the Pharmaceutical composition of existing fesoterodine to the intestines and stomach side effect。Selected pharmaceutical excipient is more common, all records in Chinese Pharmacopoeia, cheap, ample supply of commodities on the market, and the preparation method adopted is simple, mature technology, to the equipment of production without particular/special requirement。Preferred pharmaceutical excipient:
2) dextrin: under the dosage of adjuvant application, nontoxic, nonirritant。Although, significant amount is taken in and is likely to be harmful to, but larger dose has no untoward reaction for nutritional supplementation, and LD50 (mice, IV): 0.35g/kg；Take in GRAS, close at FDA " inactive ingredients guide "。Maltodextrin: the safety of the food composition (meeting existing GMP specification) that maltodextrin is direct-edible with people is suitable, nontoxic, nonirritant。Mannitol: mannitol is not substantially by gastrointestinal absorption, but can cause osmotic diarrhea time heavy dose of。List GRAS in。Allow in Europe to apply as food additive。Loaded FDA " inactive ingredients guide "。LD50 (mice, IP): 14g/kg；LD50 (mice, IV): 7.47g/kg；LD50 (mice, oral): 22g/kg；LD50 (rat, IV): 9.69g/kg；LD50 (rat, oral): 13.5g/kg。Propylene glycol: it is generally acknowledged nontoxic low irritant。Animal toxicity data are as follows: LD50 (mice, lumbar injection): 9.72g/kg；LD50 (mice, intravenous injection): 6.63g/kg；LD50 (mice, oral): 22.0g/kg；LD50 (mice, subcutaneous injection): 17.34g/kg；LD50 (rat, intramuscular injection): 0.01g/kg；LD50 (rat, lumbar injection): 6.66g/kg；LD50 (rat, intravenous injection): 6.42g/kg；LD50 (Oral Administration in Rats): 0.02g/kg；LD50 (rat, subcutaneous injection): 22.5g/kg。
Detailed description of the invention
Detailed description below is only used for the present invention is described, those skilled in the art are under the premise understanding spirit of the present invention, according to the prior art of the art and knowledge, the present invention can being converted accordingly, these technical schemes each fall within the scope of the present invention。
Unreceipted actual conditions person in example below, conventionally condition carries out, agents useful for same or the unreceipted production firm person of instrument, be can pass through city available from conventional products。The fumaric acid fesoterodine used in embodiment is our company's self-control, former grinds product fumaric acid fesoterodine slow releasing tabletProduce for Pfizer (Pfizer) company。
Embodiment 1
Using dextrin as stabilizer, preparing fumaric acid fesoterodine slow releasing tablet, its prescription is in Table 1 (1000 amounts):
Table 1
| Fumaric acid fesoterodine | 4g |
| Dextrin | 120g |
| Lactose | 65g |
| Microcrystalline Cellulose | 25g |
| Hypromellose K15M | 50g |
| Hypromellose K100M | 50g |
| Glyceryl Behenate | 15g |
Its preparation method is as follows:
Weigh supplementary material according to table 1, take fumaric acid fesoterodine and dextrin mixing, cross 100 mesh sieve mix homogeneously, then mix and cross 100 mesh sieves with lactose, microcrystalline Cellulose, hypromellose and mix homogeneously。Mixed powder adds 95% ethanol and makes wetting agent, soft material processed, crosses 20 mesh sieve wet granulars, and wet granular is dried to moisture less than 4.0% through 45 DEG C, obtains dry granule。Dry granule crosses 20 mesh sieve granulate, puts in blender by dry granule, adds Glyceryl Behenate, mixing, tabletting。Element sheet is adopted film coating, and coating material selects stomach dissolution type coating material Opadry 259F680000, and coating method is as follows:
Being put by water and at the uniform velocity stir under agitator to swirling occur, be slowly added to coating material along whirlpool outer rim, stirring makes to be uniformly dispersed, and uses, filter through 80 eye mesh screens before using after maintaining stirring 1 hour。Being put by label in coating pan and preheat, regulate suitable rotating speed, drum hot blast (controlling about about 60 DEG C), label temperature controls 35～45 DEG C；Regulating the pressure, inlet temperature, coating solution flow velocity and the pot rotating speed that are suitable for, label temperature controls 35～45 DEG C, carries out coating；According to precoating situation, the coating parameter remaining certain carries out coating, observes coating situation (label temperature, prevent bonding die, flower sheet) at any time and and does corresponding parameter adjustment, terminate to coating in coating process, final controls coating weight gain 2%～4%。
Embodiment 2
Making stabilizer with maltodextrin, prepare fumaric acid fesoterodine slow releasing tablet, its prescription is in Table 2 (1000 amounts):
Table 2
| Fumaric acid fesoterodine | 4g |
| Maltodextrin | 100g |
| Lactose | 65g |
| Microcrystalline Cellulose | 25g |
| Hypromellose K15M | 50g |
| Hypromellose K100M | 50g |
| Pulvis Talci | 9g |
Its preparation method is as follows:
Weigh supplementary material with reference to table 2, take fumaric acid fesoterodine and maltodextrin mixing, cross 120 mesh sieve mix homogeneously, then mix homogeneously with lactose, microcrystalline Cellulose, hypromellose mixing 40 mesh sieves；Mixed powder adds, and 80% ethanol makes wetting agent, soft material processed, crosses 14 mesh sieve wet granulars, and wet granular is dried to moisture less than 4.0% through 45 DEG C, obtains dry granule。Dry granule crosses 14 mesh sieve granulate, puts in blender by dry granule, adds Glyceryl Behenate, mixing, tabletting。Element sheet is adopted film coating, and coating material selects stomach dissolution type coating material Opadry 259F680000, and coating method is as follows:
Water is put and at the uniform velocity stirs to swirling occurs under agitator；Being slowly added to coating material along whirlpool outer rim, stirring makes to be uniformly dispersed, and uses, filter through 80 eye mesh screens before using after maintaining stirring 1 hour。Being put by label in coating pan and preheat, regulate suitable rotating speed, drum hot blast (controlling about about 60 DEG C), label temperature controls 35～45 DEG C；Regulating the pressure, inlet temperature, coating solution flow velocity and the pot rotating speed that are suitable for, label temperature controls 35～45 DEG C, carries out coating；According to precoating situation, the coating parameter remaining certain carries out coating, observes coating situation (label temperature, prevent bonding die, flower sheet) at any time and and does corresponding parameter adjustment, terminate to coating in coating process, final controls coating weight gain 2%～4%。
Embodiment 3
With mannitol used as stabilizers, preparing fumaric acid fesoterodine slow releasing tablet, its prescription is in Table 3 (1000 amounts):
Table 3
| Fumaric acid fesoterodine | 4g |
| Mannitol | 80g |
| Lactose | 65g |
| Microcrystalline Cellulose | 25g |
| Hypromellose K15M | 50g |
| Hypromellose K100M | 50g |
| Glyceryl Behenate | 12g |
| Magnesium stearate | 3g |
Its preparation method is as follows:
Weigh supplementary material with reference to table 3, take fumaric acid fesoterodine and mannitol mixing, cross 40 mesh sieve mix homogeneously, then mix homogeneously with lactose, microcrystalline Cellulose, hypromellose mixing 100 mesh sieves；Mixed powder adds 100% ethanol and makes wetting agent, soft material processed, crosses 20 mesh sieve wet granulars, and wet granular is dried to moisture less than 4.0% through 45 DEG C。Granule must be done；Dry granule crosses 20 mesh sieve granulate, puts in blender by dry granule, adds Glyceryl Behenate, mixing, tabletting。Element sheet is adopted film coating, and coating material selects stomach dissolution type coating material Opadry 259F680000, and coating method is as follows:
Water is put and at the uniform velocity stirs to swirling occurs under agitator；Being slowly added to coating material along whirlpool outer rim, stirring makes to be uniformly dispersed, and uses, filter through 80 eye mesh screens before using after maintaining stirring 1 hour。Being put by label in coating pan and preheat, regulate suitable rotating speed, drum hot blast (controlling about about 60 DEG C), label temperature controls 35～45 DEG C；Regulating the pressure, inlet temperature, coating solution flow velocity and the pot rotating speed that are suitable for, label temperature controls 35～45 DEG C, carries out coating；According to precoating situation, the coating parameter remaining certain carries out coating, observes coating situation (label temperature, prevent bonding die, flower sheet) at any time and and does corresponding parameter adjustment, terminate to coating in coating process, final controls coating weight gain 2%～4%。
Embodiment 4
With propylene glycol used as stabilizers, preparing fumaric acid fesoterodine slow releasing tablet, its prescription is in Table 4 (1000 amounts):
Table 4
| Fumaric acid fesoterodine | 4g |
| Propylene glycol | 10g |
| Lactose | 65g |
| Microcrystalline Cellulose | 25g |
| Hypromellose K15M | 50g |
| Hypromellose K100M | 50g |
| Glyceryl Behenate | 15g |
Its preparation method is as follows:
Weigh supplementary material with reference to table 4, take fumaric acid fesoterodine and cross 100 mesh sieves, take lactose, microcrystalline Cellulose, hypromellose mixing 100 mesh sieve mix homogeneously；Propylene glycol is added in 95% ethanol, mixing, to make wetting agent, soft material processed, cross 20 mesh sieve wet granulars, wet granular is dried to moisture less than 4.0% through 45 DEG C。Granule must be done；Dry granule crosses 20 mesh sieve granulate, puts in blender by dry granule, adds Glyceryl Behenate, mixing, tabletting。Element sheet is adopted film coating, and coating material selects stomach dissolution type coating material Opadry 259F680000, and coating method is as follows:
Water is put and at the uniform velocity stirs to swirling occurs under agitator；Being slowly added to coating material along whirlpool outer rim, stirring makes to be uniformly dispersed, and uses, filter through 80 eye mesh screens before using after maintaining stirring 1 hour。Being put by label in coating pan and preheat, regulate suitable rotating speed, drum hot blast (controlling about about 60 DEG C), label temperature controls 35～45 DEG C；Regulating the pressure, inlet temperature, coating solution flow velocity and the pot rotating speed that are suitable for, label temperature controls 35～45 DEG C, carries out coating；According to precoating situation, the coating parameter remaining certain carries out coating, observes coating situation (label temperature, prevent bonding die, flower sheet) at any time and and does corresponding parameter adjustment, terminate to coating in coating process, final controls coating weight gain 2%～4%。
Embodiment 5
With sucrose used as stabilizers, preparing fumaric acid fesoterodine slow releasing tablet, its prescription is in Table 5 (1000 amounts):
Table 5
| Fumaric acid fesoterodine | 4g |
| Sucrose | 20g |
| Lactose | 65g |
| Microcrystalline Cellulose | 25g |
| Hypromellose K15M | 50g |
| Hypromellose K100M | 50g |
| Glyceryl Behenate | 15g |
Its preparation method is as follows:
Weigh supplementary material with reference to table 5, take fumaric acid fesoterodine and sucrose mixing, cross 100 mesh sieve mix homogeneously, then mix homogeneously with lactose, microcrystalline Cellulose, hypromellose mixing 100 mesh sieves；Mixed powder adds 85% ethanol and makes wetting agent, soft material processed, crosses 20 mesh sieve wet granulars, and wet granular is dried to moisture less than 4.0% through 45 DEG C。Granule must be done；Dry granule crosses 20 mesh sieve granulate, puts in blender by dry granule, adds Glyceryl Behenate, mixing, tabletting。Element sheet is adopted film coating, and coating material selects stomach dissolution type coating material Opadry 259F680000, and coating method is as follows:
Water is put and at the uniform velocity stirs to swirling occurs under agitator；Being slowly added to coating material along whirlpool outer rim, stirring makes to be uniformly dispersed, and uses, filter through 80 eye mesh screens before using after maintaining stirring 1 hour。Being put by label in coating pan and preheat, regulate suitable rotating speed, drum hot blast (controlling about about 60 DEG C), label temperature controls 35～45 DEG C；Regulating the pressure, inlet temperature, coating solution flow velocity and the pot rotating speed that are suitable for, label temperature controls 35～45 DEG C, carries out coating；According to precoating situation, the coating parameter remaining certain carries out coating, observes coating situation (label temperature, prevent bonding die, flower sheet) at any time and and does corresponding parameter adjustment, terminate to coating in coating process, final controls coating weight gain 2%～4%。
Embodiment 6
With dextrin and mannitol used as stabilizers, making fumaric acid fesoterodine slow releasing tablet, its prescription is in Table 6 (1000 amounts):
Table 6
| Fumaric acid fesoterodine | 4g |
| Dextrin | 100g |
| Mannitol | 40g |
| Lactose | 65g |
| Microcrystalline Cellulose | 25g |
| Hypromellose K15M | 50g |
| Hypromellose K100M | 50g |
| Magnesium stearate | 9g |
Its preparation method is as follows:
Weigh supplementary material with reference to table 6, take fumaric acid fesoterodine, dextrin and mannitol mixing, cross 100 mesh sieve mix homogeneously, then mix homogeneously with lactose, microcrystalline Cellulose, hypromellose mixing 100 mesh sieves；Mixed powder adds 90% ethanol and makes wetting agent, soft material processed, crosses 20 mesh sieve wet granulars, and wet granular is dried to moisture less than 4.0% through 45 DEG C。Granule must be done；Dry granule crosses 20 mesh sieve granulate, puts in blender by dry granule, adds Glyceryl Behenate, mixing, tabletting。Element sheet is adopted film coating, and coating material selects stomach dissolution type coating material Opadry 259F680000, and coating method is as follows:
Water is put and at the uniform velocity stirs to swirling occurs under agitator；Being slowly added to coating material along whirlpool outer rim, stirring makes to be uniformly dispersed, and uses, filter through 80 eye mesh screens before using after maintaining stirring 1 hour。Being put by label in coating pan and preheat, regulate suitable rotating speed, drum hot blast (controlling about about 60 DEG C), label temperature controls 35～45 DEG C；Regulating the pressure, inlet temperature, coating solution flow velocity and the pot rotating speed that are suitable for, label temperature controls 35～45 DEG C, carries out coating；According to precoating situation, the coating parameter remaining certain carries out coating, observes coating situation (label temperature, prevent bonding die, flower sheet) at any time and and does corresponding parameter adjustment, terminate to coating in coating process, final controls coating weight gain 2%～4%。
Embodiment 7
Comparative example 1: do the preparation (according to Chinese patent CN101466371A preparation method) of stabilizer fumaric acid fesoterodine tablet with xylitol, element tablet recipe is in Table 7 (1000 amounts):
Table 7
| Fumaric acid fesoterodine | 4g |
| Xylitol | 40g |
| Lactose | 90g |
| Microcrystalline Cellulose | 30g |
| Hypromellose K15M | 70g |
| Hypromellose K100M | 70g |
| Glyceryl Behenate | 8g |
| Pulvis Talci | 8g |
Its preparation method is as follows:
Weigh supplementary material with reference to table 7, take fumaric acid fesoterodine and xylitol mixing, cross 100 mesh sieve mix homogeneously。Being put by mixed powder in mixer-granulator and mix 1 minute, when stirring, add water and make wetting agent soft material, cross 20 mesh sieve wet granulars, wet granular is dried to moisture less than 0.5% through 45 DEG C。Granule must be done；Dry granule crosses 20 mesh sieve granulate, mixing；The lactose microcrystal cellulose adding recipe quantity successively in granule mixes 10 minutes, add hypromellose (K4M and K100M), Glyceryl Behenate and Pulvis Talci to mix 1 minute, after mixture is crossed 50 mesh sieves, put in blender and mix 15 minutes, take above-mentioned ready press sheet mixture to be transferred in rotary tablet machine, and be pressed into ellipse and double-convex tablet；Take element coating tablets, at the uniform velocity stir to swirling occurs under Jiang Shui puts agitator；Being slowly added to coating material along whirlpool outer rim, stirring makes to be uniformly dispersed, and uses, filter through 80 eye mesh screens before using after maintaining stirring 1 hour。
Label is put in coating pan and is preheated by coating, regulates suitable rotating speed, drum hot blast (controlling about about 60 DEG C), and label temperature controls 35～45 DEG C；Regulating the pressure, inlet temperature, coating solution flow velocity and the pot rotating speed that are suitable for, label temperature controls 35～45 DEG C, carries out coating；According to precoating situation, the coating parameter remaining certain carries out coating, observes coating situation (label temperature, prevent bonding die, flower sheet) at any time and and does corresponding parameter adjustment, terminate to coating in coating process, final controls coating weight gain 2%～4%。
Embodiment 8
Comparative example 2: the preparation (the plain sheet that in prescription, not prepared by plus antacid stabilizer) of fumaric acid fesoterodine tablet, and element tablet recipe is in Table 8 (1000 amounts):
Table 8
| Fumaric acid fesoterodine | 4g |
| Lactose | 90g |
| Microcrystalline Cellulose | 30g |
| Hypromellose K15M | 70g |
| Hypromellose K100M | 70g |
| Glyceryl Behenate | 8g |
| Pulvis Talci | 8g |
Its preparation method is as follows:
Weigh supplementary material with reference to table 8, take fumaric acid fesoterodine and cross 100 mesh sieves, mix and cross 100 mesh sieves with lactose, microcrystalline Cellulose, hypromellose and mix homogeneously；Mixed powder adds 95% ethanol and makes wetting agent, soft material processed, crosses 20 mesh sieve wet granulars, and wet granular is dried to moisture less than 4.0% through 45 DEG C。Granule must be done；Dry granule crosses 20 mesh sieve granulate, puts in blender by dry granule, adds Glyceryl Behenate, Pulvis Talci, mixing, tabletting。Element sheet is adopted film coating, and coating material selects stomach dissolution type coating material Opadry 259F680000, coating method is as follows:
Water is put and at the uniform velocity stirs to swirling occurs under agitator；Being slowly added to coating material along whirlpool outer rim, stirring makes to be uniformly dispersed, and uses, filter through 80 eye mesh screens before using after maintaining stirring 1 hour。Being put by label in coating pan and preheat, regulate suitable rotating speed, drum hot blast (controlling about about 60 DEG C), label temperature controls 35～45 DEG C；Regulating the pressure, inlet temperature, coating solution flow velocity and the pot rotating speed that are suitable for, label temperature controls 35～45 DEG C, carries out coating；According to precoating situation, the coating parameter remaining certain carries out coating, observes coating situation (label temperature, prevent bonding die, flower sheet) at any time and and does corresponding parameter adjustment, terminate to coating in coating process, final controls coating weight gain 2%～4%。
Embodiment 9
Each influence factor test has the comparison of related substance
With reference to Chinese Pharmacopoeia two the annex XIXC of version in 2010 method to pharmaceutical preparation stability test guideline, the sample of embodiment is respectively placed in illumination, 60 DEG C, high humidity 75%, under high humidity 92.5% condition, related substance is had in 10 days sampling and measuring, with 0 day results contrast, relevant substance-measuring method was as follows:
(Chinese Pharmacopoeia two annex V D of version in 2010) are tested according to high performance liquid chromatography
Chromatographic condition: with octadecylsilane chemically bonded silica for filler, mobile phase A is the potassium dihydrogen phosphate (with phosphoric acid,diluted tune pH value to 2.5) of 0.01mol/L, and Mobile phase B is acetonitrile, and according to the form below carries out gradient elution；Flow velocity is 1.0ml/min, column temperature 25 DEG C, and detection wavelength is 220nm。
There is related substance (catabolite) algoscopy: take this product fine powder appropriate, accurately weighed, add diluent (taking mobile phase A and Mobile phase B to mix by 3:1, to obtain final product) and make every 1ml solution containing 0.5mg, as need testing solution。Taking need testing solution 20 μ l, inject chromatograph of liquid, record chromatogram, to 2.5 times of retention time, measures its amount of degradation products (%) by areas of peak normalization method。
The each influence factor's test of table 9 has related substance comparative result
Being can see that by the above results, the made sample of the present invention adds the embodiment 1,2,3,4,5,6 of antiacid stabilizer has related substance change all little than the comparative example 2 being not added with, with comparative example 1 and former grind productQuite even less, stability is better。Especially embodiment 1 preferably, has impurity to increase in 10 days though placing, but grinds product with formerCompare all less。
Embodiment 10
Above-described embodiment 1,2,3,4,5,6 and comparative example 1,2 carry out vitro release experiment, and assay method is as follows:
With reference to Chinese Pharmacopoeia two annex XD drug release determination method the first methods of version in 2010, selecting phosphate buffer (pH6.8) 900ml is release medium, slurry processes measures attached sedimentation basket, rotating speed is 75rpm; takes this product and puts in digestion instrument, measures in accordance with the law, samples 10ml (simultaneously supplementing synthermal isopyknic buffer) respectively at 1h, 2h, 4h, 8h, 12h, 16h, 24h; gained sample filters through 0.45 μm of microporous filter membrane, takes subsequent filtrate as need testing solution；Separately take fumaric acid fesoterodine reference substance appropriate (about 10mg), accurately weighed, add medium and dissolve and dilute and make every 1ml solution containing about fumaric acid fesoterodine 4mg, as reference substance solution。According to high performance liquid chromatography, precision measures each 100 μ l of above-mentioned solution, is injected separately into chromatograph of liquid, records chromatogram, by external standard method with the calculated by peak area every cumulative release amount at different time。
Chromatographic condition is as follows:
With octadecylsilane chemically bonded silica for filler；It is mobile phase with phosphate buffer pH7.2 (weighing disodium hydrogen phosphate 3.58g, add water 1000 dissolvings, adds 1.5ml triethylamine, with phosphorus acid for adjusting pH to 7.2)-acetonitrile (50:50)；Detection wavelength is 220nm；Theoretical cam curve must not lower than 2500 by fesoterodine。
Table 10 vitro release experimental result
Each embodiment is from drug release determination result it can be seen that in each embodiment burst size of each time period all quite, meet the designing requirement of Chinese Pharmacopoeia two annex XIXD slow releasing preparation of version in 2010, and namely the technology of the present invention is feasible。
In sum, the Pharmaceutical composition of the fumaric acid fesoterodine of the present invention has good stability, and technique preparation is simple, technology maturation, is conducive to prescription molding, and cost is low, obtained fumaric acid fesoterodine slow releasing tablet can not only solve the technical problem that principal agent fumaric acid fesoterodine is degradable, and this product pharmaceutical composition is 24h slow releasing preparation, taking convenience, it is simple to patient accepts clinic。
The foregoing is only presently preferred embodiments of the present invention, not in order to limit the present invention, all within the spirit and principles in the present invention, any amendment of making, equivalent replacement, improvement etc., should be included within protection scope of the present invention。
Claims (10)
1. the Pharmaceutical composition containing fesoterodine, it is characterised in that described Pharmaceutical composition also includes stabilizer, described stabilizer is dextrin, maltodextrin, mannitol, propylene glycol and/or sucrose。
2. Pharmaceutical composition according to claim 1, it is characterised in that described stabilizer is dextrin, maltodextrin, mannitol or propylene glycol。
3. Pharmaceutical composition according to claim 2, it is characterised in that described stabilizer is dextrin or maltodextrin。
4. the Pharmaceutical composition according to claims 1 to 3 any one, it is characterised in that the weight ratio of described stabilizer and fesoterodine is 0.10～50:1。
5. Pharmaceutical composition according to claim 1, it is characterised in that also include medicinal acceptable filler, binding agent, disintegrating agent, lubricant and/or stomach dissolution type thin film coating material。
6. Pharmaceutical composition according to claim 1, it is characterised in that described fesoterodine comprises its pharmaceutically acceptable salt, described salt is two or tricarboxylate, or be partly hydrogenated two or tricarboxylic salt。
7. Pharmaceutical composition according to claim 6, it is characterised in that the pharmaceutically acceptable salt of described fesoterodine is fumaric acid fesoterodine。
8. Pharmaceutical composition according to claim 7, it is characterised in that the weight ratio of described stabilizer and described fumaric acid fesoterodine is 5～30:1。
9. the preparation method of the Pharmaceutical composition containing fesoterodine, it is characterised in that comprise the following steps:
1) with the stabilizer in claim 1, fesoterodine is crossed 40～120 mesh sieves to mix homogeneously, then cross 40～120 mesh sieves with filler, binding agent and disintegrating agent and mix homogeneously；
2) making wetting agent with the aqueous solution of ethanol, said mixture material carries out soft material processed, cross 18～30 mesh sieve wet granulars, wet granular dries to obtain dry granule through 40 DEG C to 60 DEG C；
3) step 2 is taken) dry granule crosses 14～20 mesh sieve granulate, adds lubricant mixing, then tabletting；
4) carry out coating with stomach dissolution type thin film coating material, obtain Pharmaceutical composition。
10. the preparation method of Pharmaceutical composition according to claim 9, it is characterized in that, step 2) described wetting agent be volumetric concentration is the alcoholic solution of 80～100%, step 3) described lubricant is selected from Glyceryl Behenate, Pulvis Talci and/or magnesium stearate。
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| CN110151720A (en) * | 2019-05-09 | 2019-08-23 | 合肥信风科技开发有限公司 | Pharmaceutical composition and preparation method thereof containing fesoterodine |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101466371A (en) * | 2006-06-09 | 2009-06-24 | 施瓦茨制药有限公司 | Stabilized pharmaceutical compositions comprising fesoterodine |
| US20130236544A1 (en) * | 2012-03-08 | 2013-09-12 | Dr. Reddy's Laboratories Ltd. | Stable pharmaceutical compositions of fesoterodine |
| US20140248351A1 (en) * | 2011-04-08 | 2014-09-04 | Lek Pharmaceuticals D.D. | Pharmaceutical composition comprising fesoterodine |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101466371A (en) * | 2006-06-09 | 2009-06-24 | 施瓦茨制药有限公司 | Stabilized pharmaceutical compositions comprising fesoterodine |
| US20140248351A1 (en) * | 2011-04-08 | 2014-09-04 | Lek Pharmaceuticals D.D. | Pharmaceutical composition comprising fesoterodine |
| US20130236544A1 (en) * | 2012-03-08 | 2013-09-12 | Dr. Reddy's Laboratories Ltd. | Stable pharmaceutical compositions of fesoterodine |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110151720A (en) * | 2019-05-09 | 2019-08-23 | 合肥信风科技开发有限公司 | Pharmaceutical composition and preparation method thereof containing fesoterodine |
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