CN104721188A - Stable composition containing Alogliptin benzoate - Google Patents
Stable composition containing Alogliptin benzoate Download PDFInfo
- Publication number
- CN104721188A CN104721188A CN201310710569.2A CN201310710569A CN104721188A CN 104721188 A CN104721188 A CN 104721188A CN 201310710569 A CN201310710569 A CN 201310710569A CN 104721188 A CN104721188 A CN 104721188A
- Authority
- CN
- China
- Prior art keywords
- weight portion
- syr
- compositions
- magnesium stearate
- microcrystalline cellulose
- 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.)
- Pending
Links
Abstract
The invention relates to a composition containing Alogliptin benzoate. The composition comprises Alogliptin benzoate, mannitol, microcrystalline cellulose, hydroxy propyl cellulose, cross-linked sodium carboxymethyl cellulose and magnesium stearate. An oral solid preparation can be prepared from the composition through dry granulation or direct powder compression, which can effectively prevent increase of the content of unknown degradable impurities. Thus, the composition has better clinical treatment effect and clinical medication safety.
Description
Technical field
The invention belongs to technical field of medicine, be specifically related to a kind of compositions containing SYR-322 and prepare the method for oral solid formulation.
Background technology
Diabetes are a kind of chronic diseases perplexing the whole world, and about there are 2.3 hundred million patients in the current whole world, estimates that diabetics number in 2025 will be increased to 300,000,000.The many sequela at 35 ~ 40 years old of type 2 diabetes mellitus, account for diabetic more than 90%.But along with growth in the living standard, the sickness rate of diabetes even in child also has the trend of rising in recent years.China's diabetics nearly 9,300 ten thousand, accounts for 1/3 of global diabetics sum.
The medicine controlled for type 2 diabetes mellitus patient blood glucose of current approved listing mainly contains metformin, Insulin secretagogues, alpha-glucosidase inhibitor, Thiazolidinediones, DPP-IV(serine protease DPP IV) inhibitor, GLP-1(glucagon-like peptide 1) receptor stimulating agent and insulin etc.Find effective glycemic control agents, minimizing complication and death are the targets of global treating diabetes field research and development always.
Wherein, the transmembrane protein molecule of the anchor that DPP-IV is made up of 766 aminoacid on cell membrane, blood plasma and a lot of cell organized extensively exist, and the DPP-IV that lymphocytic cell surface exists is called as CD26(dipeptide amido peptidase TV), play an important role in immune system.DPP-IV is that one of Chief enzyme of GLP-1 degraded inactivation is impelled in inside and outside, this enzyme holds the 2nd alanine to cause its inactivation by the N being hydrolyzed GLP-1, so GLP-1 concentration can be improved after suppressing this enzyme, impel islet cells to produce insulin, reduce Glucagon concentrations simultaneously.And diabetes are the dysbolismus diseases because islet cells anoxia causes, show as blood sugar level and Plasma Glucagon Level can be in any more, insulin secretion speed and change of blood sugar bradykinesia.
SYR-322 (Alogliptin benzoate, structure is as shown in Equation 1) be the former DPP-IV inhibitor of grinding of Japanese military field (Takeda) company, significantly can suppress DPP-IV high selectivity, maintain the level of GLP-1 and glucose-dependent-insulinotropic polypeptide (GIP) in body, promote the secretion of insulin, thus play blood sugar lowering curative effect.In April, 2010, SYR-322 obtained the listing approval of Japanese MHLW, and the SYR-322 (NESINA) of Yuan Yan producer is film coating tablet, has 3 kinds of preparation specifications, and (25mg is yellow for specification different colours difference; 12.5mg micro-yellow; The light redness of the skin or complexion of 6.25mg).3 kinds of specification preparation label colors are white.
Egelieting is mainly used in the bad type 2 diabetes mellitus patient of following glycemic control: diet alone and Exercise therapy for treatment of knee joint person, and can be used alone Alogliptin; Diet and exercise therapy and alpha-glucosidase inhibitor or thiazolidinediones therapist, can add and use Egelieting.Egelieting has very strong targeting specific, and when glucose is normal, this medicine does not have activity, can not cause hypoglycemia.Egelieting is good for type 2 diabetes mellitus patient toleration, without dose-limiting toxicity, does not occur drug accumulation phenomenon when multiple dose administration, and the infull patient of Liver and kidney function is also without the need to adjusting dosage, and Pharmacokinetic Results also unable to take food thing impact.Also do not find severely adverse event and dead case under study for action, do not have patient to drop by the wayside because of untoward reaction.
The international monopoly WO2008/093878 of Japan's military field application discloses a kind of tablet and preparation method thereof, mainly for solving the technical problem of sticking.Prior art makes tablet by the method that conventional wet lay is granulated, and this patent WO2008/093878 by by SYR-322 with mannitol, microcrystalline Cellulose by mixing after prescription proportioning, spray adds hydroxypropyl cellulose aqueous solution and drying, pellet through sieves, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, magnesium stearate is added in the granule of specified particle diameter, add/or do not add light anhydrous silicic acid, tabletting, finally add that coloring agent coating obtains finished product with hypromellose.
The Chinese patent CN103156819A of SHANDONG LUOXIN PHARMACY STOCK Co., LTD.'s application discloses a kind of SYR-322 tablet formulation and preparation method thereof, it is in the preparation in the military field of Japan, disintegration rate is slow, dissolution is low and use inconvenient shortcoming to propose technical scheme: by active ingredient benzoic acid Egelieting, mannitol, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, magnesium stearate and 5% hydroxypropyl cellulose aqueous solution are mixed and made into solid preparation, this preparation method is still wet granulation.
We are through a large amount of experimentatioies, find that the former triturate in solid preparation and the Japanese military field adopting wet granulation to make is in influence factor's test and accelerated test process, all occurs yellowish, the situation that appearance character is not up to standard.Find after further study, the reason of tablet appearance color and luster change, mainly can be increased under these conditions by a unknown degradation impurity, and the stability of product is not good to be caused.This makes the quality of this product there is very large uncertainty, because diabetics needs Long-term taking medicine, the side effect brought to patient thus and risk can not and know.
This project team member is through deep research, finally have found and cause the reason of product instability (SYR-322, microcrystalline Cellulose mix with water and easily produce degradation impurity under the high temperature conditions, the generation of this degradation impurity causes the change of product appearance color), and creatively solve this problem.Seminar adopts wet granulation to change the method for dry granulation or direct powder compression into; the rising of this unknown impuritie content can be suppressed pole significance; and test under identical condition with the former product that grind, find that my Products stability is better than the former SYR-322 sheet grinding Japanese military field.
Summary of the invention
The object of this invention is to provide a kind of dry granulation or direct powder compression of adopting and prepare SYR-322 compositions method; improve the stability of SYR-322 solid preparation; safety and effectiveness, make it play therapeutical effect more safely and effectively.
The invention provides a kind of compositions containing SYR-322 adopting dry granulation to obtain, it comprises:
The compositions of 6.25mg specification comprises:
The SYR-322 of 8.5 weight portions;
The mannitol of 1-200 weight portion;
The microcrystalline Cellulose of 1-100 weight portion;
The hydroxypropyl cellulose of 1-50 weight portion;
The cross-linking sodium carboxymethyl cellulose of 1-50 weight portion;
The magnesium stearate of 0.5-50 weight portion.
The compositions of 12.5mg specification comprises:
The mannitol of 1-200 weight portion;
The microcrystalline Cellulose of 1-100 weight portion;
The hydroxypropyl cellulose of 1-50 weight portion;
The cross-linking sodium carboxymethyl cellulose of 1-50 weight portion;
The magnesium stearate of 0.5-50 weight portion.
The compositions of 25mg specification comprises:
The mannitol of 1-200 weight portion;
The microcrystalline Cellulose of 1-100 weight portion;
The hydroxypropyl cellulose of 1-50 weight portion;
The cross-linking sodium carboxymethyl cellulose of 1-50 weight portion;
The magnesium stearate of 0.5-50 weight portion.
For the SYR-322 compositions of mentioned component; the present invention also relates to the preparation method of SYR-322 compositions simultaneously: by supplementary material sieving for standby; take the SYR-322 of group component; mannitol, microcrystalline Cellulose, hydroxypropyl cellulose and cross-linking sodium carboxymethyl cellulose mix homogeneously; mixed powder dry granulating machine is carried out dry-pressing in blocks; pulverize granulate after granulating, after adding the magnesium stearate mix homogeneously of recipe quantity, tabletted.
The invention provides a kind of compositions containing SYR-322 adopting direct powder compression to obtain, it comprises:
6.25mg set of specifications compound composed as follows:
The SYR-322 of 8.5 weight portions;
The microcrystalline Cellulose of 1-100 weight portion;
The pregelatinized Starch of 1-200 weight portion
The carboxymethylstach sodium of 1-50 weight portion;
The magnesium stearate of 0.5-10 weight portion.
12.5mg set of specifications compound composed as follows:
The SYR-322 of 17 weight portions;
The microcrystalline Cellulose of 1-100 weight portion;
The pregelatinized Starch of 1-200 weight portion
The carboxymethylstach sodium of 1-50 weight portion;
The magnesium stearate of 0.5-10 weight portion.
25mg set of specifications compound composed as follows:
The microcrystalline Cellulose of 1-100 weight portion;
The pregelatinized Starch of 1-200 weight portion
The carboxymethylstach sodium of 1-50 weight portion;
The magnesium stearate of 0.5-10 weight portion.
For the SYR-322 compositions of mentioned component, the present invention also relates to the method that SYR-322 compositions is prepared into oral solid formulation simultaneously, wherein, mixed powder tablet machine directly can be pressed into tablet.
In the present invention, for SYR-322 not any restriction, can be any pharmaceutically useful SYR-322.
In the present invention, for mannitol as filler, not any restriction can be any pharmaceutically useful mannitol.
In the present invention, for microcrystalline Cellulose as filler, not any restriction can be any pharmaceutically useful microcrystalline Cellulose.
In the present invention, for hydroxypropyl cellulose as binding agent, not any restriction can be any pharmaceutically useful hydroxypropyl cellulose.
In the present invention, for pregelatinized Starch as filler, not any restriction can be any pharmaceutically useful pregelatinized Starch.
In the present invention, for carboxymethylstach sodium as disintegrating agent, not any restriction can be any pharmaceutically useful carboxymethylstach sodium.
In the present invention, for magnesium stearate as lubricant, not any restriction can be any pharmaceutically useful magnesium stearate.
In the present invention, for cross-linking sodium carboxymethyl cellulose as disintegrating agent agent, not any restriction can be any pharmaceutically useful cross-linking sodium carboxymethyl cellulose.
In the present compositions, other pharmaceutically acceptable additives can also be comprised.For the restriction that the type of described additive is not concrete, can be additive conventional in this area, specifically be selected from pharmaceutically acceptable filler, pharmaceutically acceptable disintegrating agent, pharmaceutically acceptable binding agent and pharmaceutically acceptable lubricant one or more.In the present invention, for consumption not any restriction of other additives.In a preferred embodiment of the present invention, the content of described additive is 4.5-450 weight portion.
In the present invention, for type not any restriction of pharmaceutically acceptable filler, it can be filler conventional in this area.In a preferred embodiment of the present invention, described filler is selected from pregelatinized Starch, lactose, mannitol, microcrystalline Cellulose and their mixture.In another preferred embodiment of the present invention, described filler is pregelatinized Starch, microcrystalline Cellulose and their mixture.In the present invention, for consumption not any restriction of filler, it can be the conventional amount used in this area.In an example of the present invention, the consumption of described filler is 2-300 weight portion, is preferably 2-150 weight portion.
In the present invention, for the type of described disintegrating agent without any restriction, it can be pharmaceutically acceptable conventional disintegrating agents.In a preferred embodiment of the present invention, described disintegrating agent is selected from polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium and their mixture.In the present invention, the content of described disintegrating agent at 1-50 weight portion, should be preferably 1-25 weight portion, is more preferably 1-10 weight portion.
In the present invention, for the type of described binding agent without any restriction, it can be pharmaceutically acceptable traditional binders.In a preferred embodiment of the present invention, described binding agent is selected from hydroxypropyl cellulose.
In the present invention, for type not any restriction of pharmaceutically acceptable lubricant, it can be lubricant conventional in this areas such as magnesium stearate, Pulvis Talci, paraffin, glyceryl monostearate, monopalmitin.In a preferred embodiment of the present invention, described lubricant is selected from magnesium stearate.In the present invention, for consumption not any restriction of lubricant, it can be the conventional amount used in this area.In an example of the present invention, the consumption of described lubricant is 0.5-50 weight portion, is preferably 0.5-25 weight portion, is more preferably 0.5-10 weight portion.
In the present invention, term used " pharmaceutically acceptable additive " refers to the additive of pharmaceutically acceptable reinforcement formulation properties.Examples of such additives is well-known to those skilled in the art, comprise filler, disintegrating agent, binding agent, lubricant and other.Wherein filler is lactose, pregelatinized Starch and microcrystalline Cellulose etc.Disintegrating agent is cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone and carboxymethyl starch sodium etc.Binding agent is hydroxypropyl cellulose etc.Lubricant is magnesium stearate etc.
In a preferred embodiment of the present invention, the described compositions containing SYR-322 comprises:
The SYR-322 of 8.5 weight portions;
105.2 the mannitol of weight portion;
The microcrystalline Cellulose of 22.5 weight portions;
The hydroxypropyl cellulose of 4.5 weight portions;
The cross-linking sodium carboxymethyl cellulose of 7.5 weight portions;
The magnesium stearate of 1.8 weight portions.
In a preferred embodiment of the present invention, the described compositions containing SYR-322 comprises:
The SYR-322 of 8.5 weight portions;
The microcrystalline Cellulose of 95.2 weight portions;
The pregelatinized Starch of 32.5 weight portions;
The hydroxypropyl cellulose of 4.5 weight portions;
The cross-linking sodium carboxymethyl cellulose of 7.5 weight portions;
The magnesium stearate of 1.8 weight portions.
In another preferred embodiment of the present invention, the described compositions containing SYR-322 comprises:
The SYR-322 of 8.5 weight portions;
115.2 the mannitol of weight portion;
The lactose of 12.5 weight portions;
The hydroxypropyl cellulose of 4.5 weight portions;
The cross-linking sodium carboxymethyl cellulose of 7.5 weight portions;
The magnesium stearate of 1.8 weight portions.
In another preferred embodiment of the present invention, the described compositions containing SYR-322 comprises:
The SYR-322 of 8.5 weight portions;
The mannitol of 56.5 weight portions;
The pregelatinized Starch of 50 weight portions;
The microcrystalline Cellulose of 21.2 weight portions;
The hyprolose of 5.8 weight portions;
The polyvinylpolypyrrolidone of 5.5 weight portions;
The Pulvis Talci of 2.5 weight portions
In another preferred embodiment of the present invention, the described compositions containing SYR-322 comprises:
The SYR-322 of 8.5 weight portions;
105.2 the mannitol of weight portion;
29.55 the microcrystalline Cellulose of weight portion;
6.0 the carboxymethylstach sodium of weight portion
The magnesium stearate of 0.72 weight portion
In another preferred embodiment of the present invention, the described compositions containing SYR-322 comprises:
The SYR-322 of 8.5 weight portions;
The mannitol of 56.5 weight portions;
The lactose of 120 weight portions;
16.25 the microcrystalline Cellulose of weight portion;
4.5 the polyvinylpolypyrrolidone of weight portion;
The magnesium stearate of 0.75 weight portion
In another preferred embodiment of the present invention, the described compositions containing SYR-322 comprises:
The SYR-322 of 8.5 weight portions;
The lactose of 90 weight portions;
44.75 the pregelatinized Starch of weight portion;
6.0 the carboxymethylstach sodium of weight portion;
The magnesium stearate of 0.75 weight portion
The described compositions containing SYR-322 can be prepared into various oral dosage form, comprises tablet, capsule and granule.
The preparation method of the described composition tablet containing SYR-322, adopts conventional method for preparing tablet thereof all can realize, comprises dry granulation tabletting method or direct powder compression method.
The described composition capsule containing SYR-322, the preparation method of its content, adopts conventional preparation method of granules all can realize, comprises dry granulation method or powder direct mixing method.
[0039] preparation method of the described composition granule containing SYR-322, adopts conventional preparation method of granules all can realize, comprises dry granulation method.
Compositions of the present invention significantly can reduce the rising of unknown impuritie, significantly improves the stability of preparation, makes it have better clinical treatment effect and safety.
The present invention passes through stability test, measure the projects such as the former dissolution, related substance and the drug content that grind product and own product, carry out quality versus's research, result display own product is with former to grind the behavior of product In Vitro Dissolution consistent, content conformance with standard, own product stability is better than formerly grinding product.
SYR-322 sheet is former grinds product information
1. dissolution determination method
With reference to " Chinese Pharmacopoeia " version two (annex XC second method) in 2010, with water 900mL for dissolution medium, rotating speed is 50 turns per minute, operate in accordance with the law, through 30 minutes time, get solution and filter in right amount, get subsequent filtrate (sample concentration 12.5 μ g/mL) as need testing solution, it is appropriate that another precision takes SYR-322 reference substance, is diluted to the Egelieting in contrast product solution of every 1mL about containing 12.5 μ g with dissolution medium; Get above-mentioned two kinds of solution respectively and measure trap in 275nm wavelength, calculate the stripping quantity of every sheet.
2. determination of related substances method: with reference to SYR-322 raw material detection method, measure according to high performance liquid chromatography (" middle pharmacopeia " version in 2010 two annex V D).
Chromatographic condition: determined wavelength is 224nm, column temperature is 30 DEG C, and flow velocity is 1.0mL/min, and number of theoretical plate is not less than 3000 by formic acid Egelieting.
Mobile phase A is 0.1% high chloro acid solution (containing 0.3% triethylamine) (pH=3.0), and Mobile phase B is acetonitrile, shown in table specific as follows:
| Time (minute) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 80 | 20 |
| 10 | 80 | 20 |
| 20 | 55 | 45 |
| 30 | 55 | 45 |
| 31 | 80 | 20 |
| 40 | 80 | 20 |
System suitability: get each about 5mg of SYR-322 and impurity F 1008 and put in 10mL and 1000mL measuring bottle respectively, add the initial flow mutual-assistance dissolve and be diluted to scale, shake up, get above-mentioned two kinds of solution 2mL respectively to mix, precision measures mixed solution 20 μ L injection liquid chromatography, record chromatogram (peak sequence is followed successively by Egelieting, benzene first and impurity F 1008), number of theoretical plate calculates by Egelieting peak and is not less than 3000.
Algoscopy: get this product, porphyrize, precision takes in appropriate (being about equivalent to SYR-322 10mg) the 20mL volumetric flask of fine powder, adds initial flow phased soln and dilutes and put scale, filter, make every 1mL about containing the solution of 0.5mg, need testing solution; Precision measures need testing solution 20 μ L, respectively injection liquid chromatography, and record chromatogram is to 5 times of main constituent peak retention time.After deduction solvent peak, if any impurity peaks in need testing solution chromatogram, detect single maximum contaminant and total matter content.
3, content assaying method: with reference to SYR-322 raw material detection method, measure according to high performance liquid chromatography (Chinese Pharmacopoeia version in 2010 two annex V D).
Chromatographic condition is as follows with reference to the chromatographic condition of Related substances separation:
Chromatographic column: YMC C18 post
Mobile phase: acetonitrile-0.1% perchloric acid (containing 0.3% triethylamine) (pH=3.0)=20:80;
Determined wavelength: 224nm;
Column temperature: 30 DEG C;
Sample size: 20 μ L;
Method: get this product, porphyrize, precision takes fine powder appropriate (being about equivalent to SYR-322 12.5mg), in 25mL volumetric flask, adds mobile phase and dissolves and dilute and put scale, shake up filtration; Precision measures 1mL and puts in 10mL volumetric flask, and mobile phase is diluted to scale, shakes up, and obtains need testing solution.It is appropriate that another precision takes reference substance, is made in the same way of every 1mL about containing 50 μ g SYR-322 solution, product solution in contrast.Precision measures need testing solution and reference substance solution 20 μ L injection liquid chromatography, and record chromatogram, by external standard method with calculated by peak area this product content.
Accompanying drawing explanation
Fig. 1 embodiment 1, embodiment 7 and formerly grind the stripping curve of sheet 6.25mg in water;
Fig. 2 embodiment 2, embodiment 8 and formerly grind the stripping curve of sheet 12.5mg in water;
Fig. 3 embodiment 3, embodiment 9 and formerly grind the stripping curve of sheet 25mg in water.
Detailed description of the invention
Be described below in detail embodiments of the invention, it should be noted that embodiment described below is exemplary, only for explaining the present invention, and can not limitation of the present invention be interpreted as.In addition, if do not clearly not stated, adopted in the following embodiments all reagent are, and market can be buied, or can according to text or the synthesis of known method, for the reaction condition do not listed, be also that those skilled in the art easily obtain.
Embodiment 1
The prescription 1 of SYR-322 tablet
Preparation method: take the SYR-322 of recipe quantity, microcrystalline Cellulose, hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose, mix homogeneously.Mixed powder dry granulating machine is carried out dry-pressing in blocks, pulverize granulate after granulating, add magnesium stearate mixing, tabletted.
Embodiment 2
The prescription 2 of SYR-322 tablet
Preparation method: take the SYR-322 of recipe quantity, microcrystalline Cellulose, hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose, mix homogeneously.Mixed powder dry granulating machine is carried out dry-pressing in blocks, pulverize granulate after granulating, add magnesium stearate mixing, tabletted.
Embodiment 3
The prescription 3 of SYR-322 tablet
Preparation method: take the SYR-322 of recipe quantity, microcrystalline Cellulose, hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose, mix homogeneously.Mixed powder dry granulating machine is carried out dry-pressing in blocks, pulverize granulate after granulating, add magnesium stearate mixing, tabletted.
Embodiment 4
The prescription 4 of SYR-322 tablet
Preparation method: take the SYR-322 of recipe quantity, microcrystalline Cellulose, pregelatinized Starch, hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose, mix homogeneously.Mixed powder dry granulating machine is carried out dry-pressing in blocks, pulverize granulate after granulating, add magnesium stearate mixing, tabletted.
Embodiment 5
The prescription 5 of SYR-322 granule
Preparation method: take the SYR-322 of recipe quantity, mannitol, lactose, hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose, mix homogeneously.Mixed powder dry granulating machine is carried out dry-pressing, then gained stick is made granule by oscillating granulator, add magnesium stearate mixing, direct packaging becomes granule.
Embodiment 6
The prescription 6 of SYR-322 capsule
Preparation method: take the SYR-322 of recipe quantity, mannitol, lactose, hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose, mix homogeneously.Mixed powder dry granulating machine is carried out dry-pressing, then gained stick is made granule by oscillating granulator, add magnesium stearate, encapsulated after mix homogeneously.
Embodiment 7
The prescription 7 of SYR-322 tablet
Preparation method: the benzoic acid Ge Lieting taking recipe quantity, microcrystalline Cellulose, pregelatinized Starch, carboxymethylstach sodium and magnesium stearate, direct compression after mix homogeneously.
Embodiment 8
The prescription 8 of SYR-322 tablet
Preparation method: the benzoic acid Ge Lieting taking recipe quantity, microcrystalline Cellulose, pregelatinized Starch, carboxymethylstach sodium and magnesium stearate, direct compression after mix homogeneously.
Embodiment 9
The prescription 9 of SYR-322 tablet
Preparation method: the benzoic acid Ge Lieting taking recipe quantity, microcrystalline Cellulose, pregelatinized Starch, carboxymethylstach sodium and magnesium stearate, direct compression after mix homogeneously.
Embodiment 10
The prescription 10 of SYR-322 tablet
Preparation method: the benzoic acid Ge Lieting taking recipe quantity, mannitol, microcrystalline Cellulose, carboxymethylstach sodium and magnesium stearate, direct compression after mix homogeneously.
Embodiment 11
The prescription 11 of SYR-322 capsule
Preparation method: encapsulated after taking the SYR-322 of recipe quantity, lactose, microcrystalline Cellulose, polyvinylpolypyrrolidone, magnesium stearate mix homogeneously.
Embodiment 12
The prescription 12 of SYR-322 granule
Preparation method: take the SYR-322 of recipe quantity, lactose, pregelatinized Starch, carboxymethylstach sodium, after magnesium stearate mix homogeneously, direct packaging becomes granule.
Comparative example
Prepare comparative example 1, comparative example 2, comparative example 3 with embodiment 1, embodiment 2, method that embodiment 3 is identical respectively, difference is only that comparative example 1, comparative example 2, comparative example 3 adopt wet granulation.Prepare comparative example 4, comparative example 5, comparative example 6 with embodiment 7, embodiment 8, method that embodiment 9 is identical, difference is only that comparative example 4, comparative example 5, comparative example 6 adopt wet granulation.The prescription of comparative example 1 to comparative example 6 forms in table 1 to table 6.
Embodiment 1-3, embodiment 7-9 comparative example 1-6 and the former product (Japanese military field system) that grind are carried out influence factor's experiment at 60 DEG C, and respectively at 0 day, the 5th day, the 10th day sampling and measuring related substance and character, the results are shown in Table 7.
Embodiment 1-3, embodiment 7-9, comparative example 1-6 and the former product (Japanese military field system) that grind, respectively at 40 ± 2 DEG C, are carried out Acceleration study under 75 ± 5%RH, and respectively at 0 month, January, February, March, June, sampling and measuring related substance and character, the results are shown in Table 8.
Embodiment 1-3, embodiment 7-9 and the former product (Japanese military field system) that grind are measured dissolution and content results in table 9.
By embodiment 1-3, embodiment 7-9 and formerly grind product (Japanese military field system) stripping curve figure is shown in Fig. 1-3 in water.
The prescription composition of table 1 comparative example 1
The prescription composition of table 2 comparative example 2
The prescription composition of table 3 comparative example 3
The prescription composition of table 4 comparative example 4
The prescription composition of table 5 comparative example 5
The prescription composition of table 6 comparative example 6
Table 7 embodiment 1-2, comparative example 1-2 and formerly grind sheet influence factor result of the test
Table 8 embodiment 1-3, embodiment 7-9, comparative example 1-6 and formerly grind sheet accelerated test result
Table 9 embodiment 1-3, embodiment 7-9 and formerly grind sheet dissolution (medium: water) and content results
| Sample ID | Dissolution (%) | Content (%) |
| Embodiment 1 | 82 | 98.7 |
| Embodiment 2 | 83 | 97.5 |
| Embodiment 3 | 85 | 99.4 |
| Embodiment 7 | 83 | 96.5 |
| Embodiment 8 | 79 | 97.8 |
| Embodiment 9 | 89 | 98.0 |
| Formerly grind sheet 6.25mg | 85 | 98.9 |
| Formerly grind sheet 12.5mg | 87 | 99.0 |
| Formerly grind sheet 25mg | 87 | 97.8 |
As can be seen from table 7, table 8, embodiment 1-3 and embodiment 7-9 through influence factor experiment and Acceleration study after unknown degradation impurity (RRT ≈ 2.4) content without significant change, and comparative example 1-6 and the former product that grind are after influence factor's experiment and Acceleration study, unknown degradation impurity content significantly raises, the color of the increase that in embodiment 1-3 and embodiment 7-9, dry granulation significantly suppress unknown degradation impurity simultaneously medicine does not change yet, and considerably improves the stability of product.Simultaneously can find out that the quality of self-control medicine is better than formerly grinding medicine from table 7, table 8.The In Vitro Dissolution behavior of embodiment 1-3 and embodiment 7-9 can be found out and former to grind sheet consistent from table 9 and Fig. 1-3.
Although illustrate and describe embodiments of the invention above, be understandable that, above-described embodiment is exemplary, can not be interpreted as limitation of the present invention, those of ordinary skill in the art can change above-described embodiment within the scope of the invention when not departing from principle of the present invention and aim, revising, replacing and modification.
Claims (9)
1. the compositions containing SYR-322 adopting dry granulation to obtain, is characterized in that,
The compositions of 6.25mg specification comprises:
The SYR-322 of 8.5 weight portions;
The mannitol of 1-200 weight portion;
The microcrystalline Cellulose of 1-100 weight portion;
The hydroxypropyl cellulose of 1-50 weight portion;
The cross-linking sodium carboxymethyl cellulose of 1-50 weight portion;
The magnesium stearate of 0.5-50 weight portion;
The compositions of 12.5mg specification comprises:
The mannitol of 1-200 weight portion;
The microcrystalline Cellulose of 1-100 weight portion;
The hydroxypropyl cellulose of 1-50 weight portion;
The cross-linking sodium carboxymethyl cellulose of 1-50 weight portion;
The magnesium stearate of 0.5-50 weight portion;
The compositions of 25mg specification comprises:
The mannitol of 1-200 weight portion;
The microcrystalline Cellulose of 1-100 weight portion;
The hydroxypropyl cellulose of 1-50 weight portion;
The cross-linking sodium carboxymethyl cellulose of 1-50 weight portion;
The magnesium stearate of 0.5-50 weight portion.
2. the compositions containing SYR-322 adopting direct powder compression to obtain, is characterized in that,
The compositions of 6.25mg specification comprises:
The SYR-322 of 8.5 weight portions;
The microcrystalline Cellulose of 1-100 weight portion;
The pregelatinized Starch of 1-200 weight portion
The carboxymethylstach sodium of 1-50 weight portion;
The magnesium stearate of 0.5-10 weight portion;
The compositions of 12.5mg specification comprises:
The SYR-322 of 17 weight portions;
The microcrystalline Cellulose of 1-100 weight portion;
The pregelatinized Starch of 1-200 weight portion
The carboxymethylstach sodium of 1-50 weight portion;
The magnesium stearate of 0.5-10 weight portion.
The compositions of 25mg specification comprises:
The microcrystalline Cellulose of 1-100 weight portion;
The pregelatinized Starch of 1-200 weight portion
The carboxymethylstach sodium of 1-50 weight portion;
The magnesium stearate of 0.5-10 weight portion.
3. compositions as claimed in claim 1, in three specifications, the weight portion of adjuvant is preferably: mannitol: 1-100; Microcrystalline Cellulose: 1-50; Hyprolose: 1-25; Cross-linking sodium carboxymethyl cellulose: 1-25; Magnesium stearate: 0.5-25.
4. compositions as claimed in claim 2, in three specifications, the weight portion of adjuvant is preferably: microcrystalline Cellulose: 1-50; Pregelatinized Starch: 1-100; Carboxymethylstach sodium: 1-25; Magnesium stearate: 0.5-5.
5. the preparation method of compositions as claimed in claim 1; the step of described preparation method comprises: by supplementary material sieving for standby; take the SYR-322 of group component; mannitol, microcrystalline Cellulose, hydroxypropyl cellulose and cross-linking sodium carboxymethyl cellulose mix homogeneously; mixed powder dry granulating machine is carried out dry-pressing in blocks; pulverize granulate after granulating, after adding the magnesium stearate mix homogeneously of recipe quantity, tabletted.
6. the preparation method of compositions as claimed in claim 2, is characterized in that, mixed powder tablet machine is directly pressed into tablet.
7. compositions as claimed in claim 1, it is characterized in that, also comprise pharmaceutically acceptable additive, described additive is selected from one or more in pharmaceutically acceptable filler, pharmaceutically acceptable disintegrating agent, pharmaceutically acceptable binding agent and pharmaceutically acceptable lubricant.
8. compositions as claimed in claim 1, it is characterized in that, it comprises:
The SYR-322 of 8.5 weight portions;
105.2 the mannitol of weight portion;
The microcrystalline Cellulose of 22.5 weight portions;
The hydroxypropyl cellulose of 4.5 weight portions;
The cross-linking sodium carboxymethyl cellulose of 7.5 weight portions;
The magnesium stearate of 1.8 weight portions.
9. compositions as claimed in claim 2, it is characterized in that, described compositions comprises:
The SYR-322 of 8.5 weight portions;
The lactose of 120 weight portions;
16.25 the microcrystalline Cellulose of weight portion;
4.5 the polyvinylpolypyrrolidone of weight portion;
The magnesium stearate of 0.75 weight portion.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310710569.2A CN104721188A (en) | 2013-12-20 | 2013-12-20 | Stable composition containing Alogliptin benzoate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310710569.2A CN104721188A (en) | 2013-12-20 | 2013-12-20 | Stable composition containing Alogliptin benzoate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN104721188A true CN104721188A (en) | 2015-06-24 |
Family
ID=53445988
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310710569.2A Pending CN104721188A (en) | 2013-12-20 | 2013-12-20 | Stable composition containing Alogliptin benzoate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104721188A (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105203678A (en) * | 2015-07-10 | 2015-12-30 | 迪沙药业集团有限公司 | Method for measuring optical purity of R-alogliptin benzoate |
| CN106913535A (en) * | 2015-12-25 | 2017-07-04 | 江苏万邦生化医药股份有限公司 | A kind of DDP-4 inhibitor medicaments oral disintegrating tablet and preparation method thereof |
| CN107744499A (en) * | 2017-11-30 | 2018-03-02 | 常州市阳光药业有限公司 | SYR-322 oral administration solution and preparation method thereof |
| CN109348704A (en) * | 2015-07-17 | 2019-02-15 | 罗盖特公司 | Mannitol particles for directly compressing |
| CN109580835A (en) * | 2018-12-31 | 2019-04-05 | 辰欣药业股份有限公司 | A method of with the related substance of liquid chromatography for separating and determining Egelieting |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008093878A1 (en) * | 2007-02-01 | 2008-08-07 | Takeda Pharmaceutical Company Limited | Tablet preparation without causing a tableting trouble |
| WO2009147125A1 (en) * | 2008-06-03 | 2009-12-10 | Boehringer Ingelheim International Gmbh | Dpp-iv inhibitors for use in the treatment of nafld |
| WO2010015664A1 (en) * | 2008-08-06 | 2010-02-11 | Boehringer Ingelheim International Gmbh | Treatment for diabetes in patients inappropriate for metformin therapy |
| CN103156819A (en) * | 2013-03-29 | 2013-06-19 | 山东罗欣药业股份有限公司 | Benzoic acid alogliptin composition troche and preparation method thereof |
-
2013
- 2013-12-20 CN CN201310710569.2A patent/CN104721188A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008093878A1 (en) * | 2007-02-01 | 2008-08-07 | Takeda Pharmaceutical Company Limited | Tablet preparation without causing a tableting trouble |
| WO2009147125A1 (en) * | 2008-06-03 | 2009-12-10 | Boehringer Ingelheim International Gmbh | Dpp-iv inhibitors for use in the treatment of nafld |
| CN102056606A (en) * | 2008-06-03 | 2011-05-11 | 贝林格尔.英格海姆国际有限公司 | Dpp-iv inhibitors for use in the treatment of nafld |
| WO2010015664A1 (en) * | 2008-08-06 | 2010-02-11 | Boehringer Ingelheim International Gmbh | Treatment for diabetes in patients inappropriate for metformin therapy |
| CN103156819A (en) * | 2013-03-29 | 2013-06-19 | 山东罗欣药业股份有限公司 | Benzoic acid alogliptin composition troche and preparation method thereof |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105203678A (en) * | 2015-07-10 | 2015-12-30 | 迪沙药业集团有限公司 | Method for measuring optical purity of R-alogliptin benzoate |
| CN109348704A (en) * | 2015-07-17 | 2019-02-15 | 罗盖特公司 | Mannitol particles for directly compressing |
| US10828256B2 (en) | 2015-07-17 | 2020-11-10 | Roquett Freres | Mannitol granules for direct compression |
| CN109348704B (en) * | 2015-07-17 | 2022-04-19 | 罗盖特公司 | Mannitol granulate for direct compression |
| CN106913535A (en) * | 2015-12-25 | 2017-07-04 | 江苏万邦生化医药股份有限公司 | A kind of DDP-4 inhibitor medicaments oral disintegrating tablet and preparation method thereof |
| CN107744499A (en) * | 2017-11-30 | 2018-03-02 | 常州市阳光药业有限公司 | SYR-322 oral administration solution and preparation method thereof |
| CN109580835A (en) * | 2018-12-31 | 2019-04-05 | 辰欣药业股份有限公司 | A method of with the related substance of liquid chromatography for separating and determining Egelieting |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103655570B (en) | Sitagliptin and metformin compound slow release preparation and preparation method thereof | |
| ES2609469T3 (en) | Crush-resistant tablets intended to prevent accidental misuse and diversion of illegal use | |
| CN104721188A (en) | Stable composition containing Alogliptin benzoate | |
| ES2702328T3 (en) | Tablet susceptible to fight against improper use by injection | |
| CN101366692A (en) | Stable Exenatide formulation | |
| CN103070864B (en) | Repaglinide and metformin hydrochloride medicinal composition and its preparation method | |
| CN106924208A (en) | A kind of compound Dapagliflozin Metformin Extended-release Tablets and preparation method thereof | |
| ES2465496T3 (en) | Oral nocturnal insulin therapy | |
| CN102499923B (en) | Drug combination, as well as preparation method and application of same | |
| CN103156819A (en) | Benzoic acid alogliptin composition troche and preparation method thereof | |
| CN103181923B (en) | Pharmaceutical preparation comprising Repaglinide and preparation method thereof | |
| CN104644578A (en) | Sitagliptin phosphate composition tablet and preparation method thereof | |
| CN102552168B (en) | Pharmaceutical composition containing orlistat and its preparation method | |
| CN102755301A (en) | Glimepiride tablet and preparation method thereof | |
| CN104997744A (en) | High-stability capecitabine tablets and preparation method thereof | |
| CN104208028A (en) | Faropenem sodium-containing granules and preparation method thereof | |
| CN103463090A (en) | Preparation method of sitagliptin metformin hydrochloride compound preparation | |
| CN103301079B (en) | Capecitabine pharmaceutical composition and preparation method thereof | |
| CN101524355A (en) | Compound preparation of antituberculosis medicaments, and preparation method thereof | |
| CN101342146A (en) | Preparation method of glimepiride tablet | |
| CN103705515A (en) | Method for preparing pharmaceutical composition containing repaglinide and metformin hydrochloride | |
| CN104224783B (en) | A kind of pharmaceutical composition of the melbine containing Repaglinide and preparation method thereof | |
| CN114306267A (en) | Sitagliptin and metformin tablet preparation and preparation method thereof | |
| CN102218064B (en) | Pharmaceutical combination with repaglinide and metformin as active components and preparation method thereof | |
| CN104644601B (en) | Capecitabine tablet |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20150624 |
|
| WD01 | Invention patent application deemed withdrawn after publication |